NO178541B - Pharmacologically active hydrazine derivatives - Google Patents

Abstract

The invention relates to compounds of the formula <IMAGE> in which R1 and R9 are, independently of one another, hydrogen, acyl, unsubstituted or substituted alkyl, alkenyl or alkynyl; heterocyclyl; sulpho, or sulphonyl which is substituted by unsubstituted or substituted alkyl, aryl, heterocyclyl, alkoxy, which is unsubstituted or substituted, or by aryloxy; sulphamoyl which is unsubstituted or substituted on the nitrogen; or phosphoryl which is substituted by one or two radicals selected independently of one another from unsubstituted or substituted alkyl, from unsubstituted or substituted cycloalkyl, from aryl, from hydroxyl, from unsubstituted or substituted alkoxy, from cycloalkoxy and from aryloxy, with the proviso that not more than one of the radicals R1 and R9 is hydrogen; and R2 and R8 are each, independently of one another, hydrogen or one of the radicals mentioned above for R1 and R9; or the pairs of substituents R1 and R2 or R8 and R9 can each, independently of one another, form together with the nitrogen atom to which they are bonded certain heterocyclic rings; R3 and R4 are, independently of one another, hydrogen, unsubstituted or substituted alkyl or cycloalkyl; aryl; heterocyclyl; or unsubstituted or substituted alkenyl; or R3 and R4 together are unsubstituted or substituted alkylene, alkylidene or benzo-fused alkylene; R5 is hydroxyl; R6 is hydrogen; or R5 and R6 together are oxo; and R7 is unsubstituted or substituted alkyl or cycloalkyl; aryl; heterocyclyl; or unsubstituted or substituted alkenyl; as well as the salts of the said compounds where salt-forming groups are present, furthermore process for the preparation thereof, pharmaceutical products, the use as pharmaceutical composition or for the preparation of pharmaceutical products, as well as intermediates for the preparation of these compounds.

Description

The present invention relates to a new class of non-hydrolysable analogues for peptides cleavable by aspartate proteases, namely hydrazine derivatives.

The compounds are used as medicines or for the production of pharmaceutical preparations for combating environmental diseases.

The immunodeficiency AIDS ("Acquired Immunodeficiency Syndrome") is a disease with a fatal outcome. This disease is spreading all over the world to an increasing degree, above all within certain risk groups, but also beyond these risk groups. The disease affects millions of people and its causal combat is one of the most important goals of modern medicine. Until now, the retroviruses HIV-1 and HIV-2 (HIV stands for "Human Immunodeficiency Virus") could be identified as the cause of the disease and characterized molecularly biologically. For therapy, beyond the current possibilities for alleviating AIDS symptoms and certain preventive possibilities, research into preparations that affect the spread of the virus itself, without damaging the cells and tissues of the patient, is particularly interesting.

In particular, such compounds seem promising as they prevent the processing of the protein building blocks biosynthesized in the human cells into the virus and thus also the correct assembly of these building blocks into complete, infectious virions.

HIV-1 and HIV-2 both have a region in their genome that codes for a "gag protease". This "gag-protease" is responsible for the correct proteolytic cleavage of the precursor proteins which appear from the genome fragments coding for the "Groiip Specific Antigens" (gag). This releases the structural proteins of the virus core, in English "core". The "gag protease" itself is a component of a precursor protein encoded through the pol genome section in HIV-1 and HIV-2 which also contains the section for the "reverse transcriptase" and "intergras" and which is presumably cleaved autoproteolytically.

The "gag protease" cleaves the main core protein ("Major Core Protein") p24 of HIV-1 and HIV-2 preferably N-terminally from proline residues, that is in the divalent radicals Phe—Pro, Leu—Pro or Tyr—Pro. It is a protease with a catalytically active aspartate residue in the active center, a so-called aspartate protease.

When the action of the "gag protease" can be prevented, the proteins required for assembly of the virus core would no longer be available. This would entail a limitation or even a prevention of the reproduction of the virus. There is thus a need for inhibitors of the "gag protease" for use as an antiviral agent against AIDS and other retroviral diseases.

A number of "gag prosthesis" inhibitors containing central groups that do not form proteolytically cleavable peptide isosteres have already been synthesized. Until now, despite intense research, it has not been possible to find aspartate protease inhibitors that can be used in humans to combat AIDS for a larger proportion of those infected. This is due to the all-important pharmacodynamic problems. In addition to this, most "gag-prosthesis" inhibitors known to date have more than two asymmetric carbon atoms, which necessitates relatively complicated stereo-specific syntheses or isomer separations. The aim of the present application is therefore to provide a new class of inhibitors for viral aspartate proteases with a new central building block. In addition, the synthesis of this central building block must be sterically as simple as possible. Furthermore, the new central building blocks exhibit amlno groups at both ends, so that by choosing suitable substituents, for example, there are retro-inversopeptide analogue structures.

Accordingly, the present invention relates to compounds with the formula:

there

Ri and Rg independently of each other mean hydrogen, loweralkanoyl, phenyl-loweralkanoyl, phenyl-loweralkanoyl where the loweralkanoyl residue is substituted with carbamoyl, morpholino-loweralkanoyl, thio-morpholino-loweralkanoyl, pyridyl-loweralkanoyl, quinolyl-loweralkanoyl, tetrazolyl-loweralkanoyl, amino-loweralkanoyl which is substituted on the amine nitrogen with N-morpholino- or N-thiomorpholinocarbonyl, halogen-lower alkanoyl containing up to 3 halogen atoms, 2-(N-morpholinolower alkyl-carbamoyl)-lower alkyl, 2-(N-pyridyl lower alkyl-carbamoyl)-lower alkanoyl , lower alkoxycarbonyl, phenyl-lower alkoxycarbonyl, benzyloxycarbonyl, tetrahydrofuranyl lower alkoxycarbonyl, lower alkylsulfonyl, morpholinosulfonyl, thiomorpholinosulfonyl, N-pyridyl-loweralkyl-N-loweralkyl-carbamoyl, an acyl residue of an amino acid selected from glycine, alanine, valine, leucine, lsoleukln, glutamic acid and asparagine in (D)-, (L)- or (D,L)-form, where the α-amino group is unsubstituted or is acylated with one of the other ten l now mentioned R^ or Rq, provided that at most one of the residues R^ and R9 means hydrogen,

R2, R4, Re and R8 mean hydrogen,

<R>2» R4. R& °6 ^8 means hydrogen,

R 3 means lower alkyl, cyclohexyl-lower alkyl or optionally with halogen, lower alkoxy or cyano substituted phenyl lower alkyl,

R5 means hydroxy and

R7 means lower alkyl, cyclohexyl lower alkyl or optionally with halogen, lower alkoxy or cyano substituted phenyl lower alkyl,

whereby lower 1 in the definitions above means that the residues contain up to and including 7 carbon atoms,

or possibly a salt thereof.

Within the scope of the invention, in the definition of groups or residues such as lower alkyl, lower alkoxy, lower alkanoyl and so on, the term "lower" used means that the groups and residues thus defined, unless otherwise expressly stated, those with up to and including 7 and preferably even 4 carbon atoms.

Unless otherwise stated, the substituents in the residues R 1 , R 2 , R 3 , R 4 , R 7 , R s and/or R 8 occur independently of each other one or more times, in particular one to three times, for example singly.

The carbon atoms 1 substituted by R3 and R4 and R5 and Rg respectively, the compounds of formula I can, to the extent that they are asymmetric, in the same way as any further asymmetric carbon atoms present, be present in (R)—, (S)— or (R ,S) configuration. Thus, the present compounds can exist as isomeric mixtures or as pure isomers, in particular as diastereomer mixtures, enantiomer pairs or pure enantiomers. Compounds of formula I are preferred where the carbon atom substituted by R3 or hydroxy R5 exhibits (S) configuration and any further asymmetric carbon atoms present independently of each other exist in (R)-, (S)- or (R,S) configuration.

The general terms and designations used in the present description preferably have the following meanings, whereby any combinations or single residues can be used in the various definitions of the residues listed above and below instead of the general definitions.

Preferably only each time at most one of the residues R 1 and R 2 , respectively the residues R 8 and R 9 , is acyl.

The acyl groups R^ and Rq are:

lower alkanoyl such as formyl, acetyl, proplonyl, butyryl or pivaloyl,

phenyl lower alkanoyl, wherein the lower alkanoyl may be unsubstituted or substituted with carbamoyl, for example phenylacetyl, 3-phenylpropionyl, 2(R,S)-carbamoyl-3-phenylpropionyl, 3-phenyl-2-carbamoylpropionyl, 3-phenyl- or 3-a— naphthy1-2-tert-butylcarbamoyl-proplonyl,

2-imidazolinyl-, 2,3-dihydropyridyl-, piperidyl-, piperazinyl-, 2,3,5,6-tetrahydropyrazinyl-, morpholinyl-, thiomorpholinyl-, S,S-dioxo-thiomorpholinyl-, indolinyl-, isoindolinyl-, 4,5,6,7-tetrahydrolndolyl-, 1,2,3,4-tetrahydroquinolyl-, 1,2,3,4-tetrahydroisoquinolyl-, chromanyl-, thiochromanyl-, 1,2,3 ,4-tetrahydro-3,1-benzdiazinyl-, 3,4-dihydro-3H-4,1-benzoxazinyl-, 3,4-dihydro-3H-4,1-benzthiazinyl-, pyridyl-, quinolyl- or tetrazolyl- lower alkanoyl, for example pyridylcarbonyl as 2-, 3- or 4-pyridylcarbonyl, pyridylacetyl as 2-, 3- or 4-pyridylacetyl, for example quinolylcarbonyl as 2-, 3- or 4-quinolylcarbonyl, tetrazolyl loweralkanoyl as 3-(tetrazol -l-yl)propionyl, morpholino-lower alkanoyl, for example morpholinocarbonyl, such as morpholinocarbonyl, thiomorpholino-lower alkanoyl, for example thiomorpholinylcarbonyl such as thiomorpholinocarbonyl, especially particularly preferred morpholinocarbonyl, thiomorpholinocarbonyl, quinolin-2-ylcarbonyl, 3-(tetrazol-l-yl) -propionyl or 2-or 3-pyridyl acetyl;

with N-morpholino- or N-thiomorpholinocarbonyl, on the amino-nitrogen substituted amlnolavearalkanoyl, for example N-morpholino- or N-thiomorpholino-carbonylamino-lavearalkanoyl as N-morpholino- or N-thiomorpholino-carbonylamino-acetyl,

halolower alkanoyl, which preferably contains up to 3 halogen atoms, for example α-haloacetyl such as α-fluoro-, α-chloro-, α-bromo-, α-iodo-, α,α,α-trifluoro- or α,α,α -trichloroacetyl or halopropionyl such as <p>—chloro— or P-bromo-proplonyl,

2-(N-morpholinolower alkyl-carbamoyl)-lower alkanoyl as 2(R,S)-(N-(2-morpholinoethyl)-carbamoyl-3-methyl-butyryl, 2-(N-(pyridyl lower alkyl)-carbamoyl)-lower alkanoyl as 2(R,S)-(N-(2-pyridylmethyl)-carbamoyl)-3-methyl-butyryl;

lower alkoxycarbonyl, for example methoxy, ethoxy, isopropoxy, isobutoxy or tert-lower oxycarbonyl such as tert-butoxycarbonyl or isobutoxycarbonyl, phenyl-lower oxycarbonyl, particularly preferred is btmzyloxycarbonyl,

tetrahydrofuranyl lower oxycarbonyl such as 2-tetrahydrofuranylmethoxycarbonyl;

N-pyridyl-lower alkyl-N-lower alkyl-carbamoyl such as N-(2-, 3- or 4-pyridylmethyl)-N-Methylcarbamoyl;

the residue bonded over a carboxy group to an amino acid selected from glycine (H-Gly-OH), alanine (H-Ala-OH), valine (H-Val-OH), leucine (H-Leu-OH), isoleucine (H -Ile-OH), glutamine (H-Gln-OH) and asparagine (H-Asn-OH) whereby (apart from glycine) each of the aforementioned amino acids can be present in D-, L- or (D,L)—, preferably (apart from Val, which can also be in (D) or (D.L) form) can be in L form,

wherein the α-amino group can be unsubstituted or N-acylated with one of the other residues R^ or R2 except for an acyl residue of an amino acid as just defined, for example with lower alkanoyl as acetyl, with phenyl lower alkanoyl, where lower alkanoyl is unsubstituted or substituted for example with carbamoyl, and is branched or unbranched, wherein phenylacetyl is particularly preferred, with tetrazolyl-, pyridyl-, quinolyl-, morpholino or tlomorpholno, lower alkanoyl, for example pyridylcarbonyl such as 2-, 3- or 4-pyridylcarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl, quinol-2-ylcarbonyl, pyridylacetyl as 2- or 3-pyridylacetyl, morpholinoacetyl, pyridylpropionyl as 3-(2- or 3-pyridyl)propionyl, 3-morpholinopropionyl or tetrazolylpropionyl as 3-(tetrazol-1-yl) propionyl, with halogen-lower alkanoyl containing up to 3 halogen atoms, for example α-haloacetyl such as α-fluoro-, α-chloro-, α-bromo-, α-Iodo-, α,α,α-trifluoro- or α,α ,a-trichloroacetyl or haloproplonyl so m 3—Chloro- or e-bromopropionyl, with lower alkoxycarbonyl as tert-butoxycarbonyl, with phenyl-lower oxycarbonyl as benzyloxycarbonyl, with tetrahydrofuranyl-lower oxycarbonyl as 2-tetrahydrofuranyl-methoxycarbonyl, 2-(N-morpholinoloweralkyl-carbamoyl)-loweralkanoyl as 2(R ,S)-(N-(2-morpholinoethyl)-carbamoyl-3-methyl-butyryl or 2-(N(pyridyl lower alkyl)-carbamoyl)-lower alkanoyl as (2(R,S)(N-(2-pyridylmethyl)- carbamoyl)-3-methyl)-butyryl,

with lower alkylsulfonyl such as methyl or ethylsulfonyl, with morpholinosulfonyl or with thiomorpholinosulfonyl;

in particular the residue of an unsubstituted or substituted amino acid selected from N-morpholinocarbonylglycine, N-(N-(2-, 3- or 4-pyridyl)methyl-N-methylaminocarbonyl)glycine, valine, N-(trifluoroacetyl)-valine, N- phenylacetyl-valine, N-acetyl-valine, N-(3-phenylpropionyl)-valine, N-(2-carbamoyl-3-phenylpropionyl )-valine, N-(2(R,S)-carbamoyl-3-phenyl- propionyl)-valine, N-(2-, 3- or 4-pyridylcarbonyl)-valine, N-(2- or 3-pyridyl-

acetyl)-valine, N-(morpholinoacetyl )-valine, N-(3-(2- or 3-pyridyl)-propionyl)-valine, N-(3-(morpholino)-proplonyl)-valine, N-tetrahydrofurylmethoxycarbonyl- valine, N-3-(tetrazol-1-yl)-propionyl-valine, N-(quinoline-2-carbonyl)-valine, N-methoxycarbonyl-valine, N-isobutoxycarbonyl-valine, N-tert-butoxycarbonyl-valine, N-Benzyloxycarbonyl-valine, N-(morpholinocarbonyl)-valine, N-(thiomorpholinocarbonyl)-valine, N-(N-2-pyridylmethyl-N-methylaminocarbonyl)-valine, N-morpholino-carbonylamino-acetyl-valine, N— methylsulfonyl-valine, N-morpholinosulfonyl-valine, N-(N-2-pyridylmethyl)-N-methyl-amino-carbonyl)-valine, N-acetyl-leucine, N-(2-, 3- or 4-pyridylcarbonyl) -leucine, N-(4-thiomophorlinocarbonyl)-leucine, N-(4-aminobutyryl)-leucine, N-(benzyloxycarbonyl)-leucine, N-acetyl-isoleucine, N-propionyl-isoleucine, N-benzyloxy-carbonyl-glutamic acid , asparagine, N-benzyloxycarbonyl-asparagine, quinoline-2-carbonyl-asparagine and N-(morpholinocarbonyl )-asparagine, whereby the amino acid residues are preferably in (L)- or (D.L )-form, in the case of valine also in (D)-form;

Ri and Rg are selected from lower alkylsulfonyl such as methylsulfonyl, ethylsulfonyl, n-propylsulfonyl or tert-butylsulfonyl, morpholinosulfonyl and thiomorpholinosulfonyl. In particularly preferred embodiments of the invention, the morpholino or thiomorpholinosulfonyl substituent may be absent.

R3 and R7 are selected from among

lower alkyl, for example methyl, ethyl, propyl, isopropyl, n-butyl or tert-butyl,

cyclohexyl lower alkyl such as -methyl or -ethyl,, preferably cyclohexylmethyl and

phenyl lower alkyl which is unsubstituted or substituted by halogen, for example fluorine or chlorine, lower alkoxy, for

for example methoxy or cyano, such as benzyl, 2-phenylethyl, 3-phenylpropyl, 4-fluoro-, 4-cyano- or 4-methoxybenzyl, particularly preferred phenyl lower alkyl as just defined,

Salts of compounds of formula I are particularly acid addition salts, salts with bases or, when several salt-forming groups are present, possibly also mixed salts or inner salts.

Salts are a first series of pharmaceutically acceptable non-toxic salts of compounds of formula I.

Such salts are formed, for example, by compounds of formula I with an acidic group, for example a carboxy-, sulfo- or phosphoryl group substituted by one or two hydroxy groups, and are, for example, salts with suitable bases that are non-toxic, from metals from groups Ia . formed with organic amines, such as optionally with hydroxy substituted mono-, di- or trialkylamines, especially mono-, di- or trilower alkylamines, or with quaternary ammonium compounds, for example with N-methyl-N-ethylamine, dlethylamine, triethylamine, mono -, bis-or tris-(2-hydroxylower alkyl)amines such as mono-, bis-or tris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine or tris-(hydroxymethyl)methylamine, N,N-dilower alkyl -N-(hyd oxylaverealalkylamines such as N,N-dimethyl-N-(2-hydroxyethyl)amine or tri-(2-hydroxyethyl)amine, N-methyl-D-glucamine or quaternary ammonium salts such as tetrabutylammonium salts. The compounds of formula I with a basic group, for example an amino group, can form acid addition salts, for example with inorganic acids, for example halohydrogen acids, such as hydrochloric, sulfuric or phosphoric acid, or with organic carbonic, sulphonic, sulpho or phosphoric acids or N -substituted sulfamic acids such as acetic, propionic, glycolic, succinic, maleic, hydroxymaleic, methylmaleic, fumaric, malic, tartaric, gluconic, glucaric, glucuronic, citric, benzo-, cinnamic, mandelic, salicylic, 4-amlnosalicy1-, 2-phenoxybenzo-, 2-acetoxybenzo-, embonic, nicotinic or lsonicotinic acid, further with amino acids such as the previously mentioned ot-amlnoic acids, in particular glutamic acid or aspartic acid, as well as with methane-, ethane-, 2-hydroxy-ethane-, ethane-1,2-di-, benzene-, 4-methylbenzene- or naphthalene-2-sulfonic acid, 2- or 3-phosphoglycerate, glucose -6-phosphate, N-cyclohexylsulfamic acid (during formation of the cyclamates) or with other acidic organic compounds such as ascorbic acid. The compounds of formula I with acidic and basic groups can also form internal salts.

Pharmaceutically unsuitable salts can also be used for isolation or purification.

The compounds according to the invention exhibit an inhibitory effect on viral aspartate proteases, in particular a gag protease inhibitory effect. In the first line, in the subsequently described samples, in concentrations of 10"^ to 10"^ mol/l, they inhibit the action of gag protease from HIV-1 and HIV-2 and are therefore suitable as a remedy against diseases caused by these and the retroviruses used , for example against AIDS.

The ability of the compounds of formula I to inhibit the proteolytic activity of, for example, HIV-1 protease can be demonstrated, for example, according to that of J. Hansen et al. in "The EMBO Journal", 7, 1785-1791 (1988), described method. Thereby, the inhibition of the action with gag protease is measured on a substrate which is a fusion protein expressed in E. coil from the gag precursor protein and MS-2. The substrate and its cleavage products are separated by polyacrylamide gel electrophoresis and visualized by immunoblotting with monoclonal antibodies against MS-2.

In an even simpler test, which enables accurate quantitative statements, a synthetic peptide corresponding to the cleavage site of the gag precursor protein is used as substrate for the gag protease. This substrate and its cleavage products can be measured by HPLC.

For example, as a substrate for a recombinant HIV-1 protease (preparation according to S. Billich et al. in "J. Biol. Chem.", 263(34), 17905-17908 (1990)) a synthetic chromophore is used peptide (for example, HKARVL[N02]FEANleS (Bachem, Switzerland) or an icosapeptide such as RRSNQVSQNYPIVQNIQGRR (prepared by peptide synthesis according to known methods), which corresponds to one of the cleavage sites of the gag precursor protein. This substrate and its cleavage products can be measured by HPLC.

For this purpose, an Inhibitor with formula I to be tested is dissolved in dlmethylsulphoxide; the enzyme test is carried out by adding suitable dilutions of the inhibitor in 20 mM ε-morpholinoethanesulfonic acid (MES) buffer, pH 6.0, to the assay mixture of 67.2 pM of the above-mentioned chromophoric peptide in 0.3 M sodium acetate, 0, 1M NaCl, pH 7.4 or 122 pM of the above-mentioned icosapeptide in 20 mM MES buffer, pH 6.0. The size of the batch is 100 pl. The reaction is started by adding in the first case 2 µl, in the second case 10 µl HIV-1 protease and is stopped in the first case after 15 minutes by the addition of 100 µl 0.3M ECIO4, in the second case after one hour of incubation at 37<*>C while adding 10 µl of 0.3M HCIO4. The reaction products are quantified after centrifugation of the sample for 5 minutes at 10,000 x g in 100 µl (preparation with chromofort peptide) or 20 µl (icosapeptide preparation) respectively of the obtained supernatant and after the whole has been placed on a 125 mm x 4.6 mm Nucleosil® C18-5p-HPLC column (Macherey & Nagel, Dtlren) and elution, on the basis of the Peak height of the cleavage product at 280 (chromofort peptide) or at 215 nm (icosapeptide), gradient: 100* El.l - » 505É E1 .1 ./505É El.2

(El.1: 75* acetonitrile, 90* H 2 O, 0.1* trifluoroacetic acid (TFA); El. 2: 75* acetonitrile, 25* H 2 O, 0.08* TFA) during 15 minutes; normal flow rate 1 ml/min.

Hereby, IC5Q values (IC50 - the concentration which reduces the activity of HIV-1 protease compared to a control without inhibitor, by 50*) of approx. 10~<6> to 10~<9>M, especially at approx. IO-<7> to 10~<8>M.

In a further test, it can be demonstrated that the compounds according to the present invention protect cells normally infected by HIV from such an infection, or at least slow down such an infection. Thereby, the human T-cell leukemia cell line MT-2 ("Science", 229, 563 (1985)), which is extremely sensitive to the cytopathogenic effect of HIV, is incubated with HIV alone or with HIV 1 in the presence of the compounds of the invention after which the viability of the thus treated cells is assessed after a few days.

For this purpose, MT-2 cells are maintained in RPMI 1640 medium (Gibco, Svelts, RPMI 1640 contains an amino acid mixture without L-Gln) supplemented with 10* heat-inactivated fetal calf serum, L-glutamine, incubated (2-[4 -(2-hydroxyethyl)-1-piperazino]-ethanesulfonic acid) and standard antibiotics, at 37°C in humidified air with 5* CO 2 . 50 µl of the test compound in question in culture medium and 100 µl of HIV-1 in culture medium (800 TCID50/ml) (TCID50 - Tissue Culture Infectious Dose 50 - dose that infects 50* of the MT-2 cells) are brought to 4xl0<3 >exponentially grown MT-2 cells in 50 pl of culture medium per well of 96-well microtiter plates. Parallel aliquots on an additional microtiter plate with cells and test compound contain 100 µl culture medium without virus. After 4 days of incubation in 10 µl of cell supernatant, the reverse transcriptase (RT) activity is determined. RT activity is determined in 50 mM Tris (α,α,α-tris(hydroxymethyl)-methylamine, Ultra pur, Merck, Federal Republic of Germany) pH 7.8, 75 mM KCl, 2 mM dithiothreitol, 5 mM MgCl£; 0.05* Nonidet P-40 (Detergens; Sigma, Svelts), 50 pg/ml polyadenylic acid (Pharmacia, Sweden); 1.6 pg/ml dT( 12-18) (Sigma, Svelts). The mixture is filtered through a 0.45 µm Acrodlsc filter (Gellman Science Inc., Ann Arbor) and stored at -20°C. To an aliquot of this solution, 0.1* (v/v) [α-<32>P]dTTP is added to achieve a final radioactive activity of 10 pCi/ml. 10 µl of the culture supernatant is transferred onto a new 96-well microliter plate and to this is added 30 µl of the aforementioned RT cocktail. After mixing, the plate is incubated in lfc for 3 hours at 37<*>C. 5 µl of this reaction mixture is transferred onto Whatman DE81 paper (Whatman). The dried filter is washed three times for 5 minutes with 300 mM NaCl/25 mM trisodium chloride and once with 95* ethanol and dried again in air. The assessment takes place in a matrix Packard 96-well counter (Packard). The EDgrj values are calculated and defined as the lowest concentration of the test compound in question which lowers the RT activity by 90* compared to cell approaches that have not been treated with the test substance. The RT activity is thus a measure of HIV-1 propagation.

The compounds of the invention thereby show an EDsg value of approx. IO-<5> to 10-<8> M, preferably approx. 5 x IO-<7> to 5 x 10-<8> M.

For the groups of compounds of formula I indicated below, definitions of residues from the above general definitions can be inserted in a reasonable way, for example by replacing general with more specific definitions, or definitions from the other groups can be added or omitted.

First and foremost preferred are compounds of formula I, where Ri means tert-butoxycarbonyl, benzyloxycarbonyl, the monovalent residue of the amino acid valine bound via the carboxy group or the residue of it bound via the carboxy group on the nitrogen atom with one of the residues phenylacetyl, 3-pyridylacetyl, morpholinocarbonyl, thiomorpholinylcarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl acylated alanine, R2 means hydrogen, R3 means benzyl, R4 means hydrogen, R5 means hydroxy, Rg means hydrogen, R7 means isobutyl, cyclohexylmethyl or benzyl, Rg means hydrogen and Rg means one of those mentioned for Ri residues and the asymmetric carbon atoms carrying the residues R3 and R5 exist in the 1 S configuration, as well as the pharmacologically acceptable salts of these compounds.

Particularly preferred is a compound of formula I there

Ri and Rg mean a monovalent residue of the amino acid (L)-valine bonded above the carboxy group and acylated on the amine nitrogen with benzyloxycarbonyl,

R2, R4, Rg and Rg are hydrogen,

R3 means benzyl,

R5 means hydroxy,

R7 means isobutyl, and

the carbon atoms carrying the residues R3 and R5 exist in S-configuration,

as well as a pharmacologically acceptable salt of one of these compounds,

or a compound of formula I, wherein

Ri and Rg mean a monovalent residue of the amino acid (L)-valine bonded above the carboxy group and acylated on the amln nitrogen with benzyloxycarbonyl,

<R>2» R4» R6 °6 R8 means hydrogen,

R3 means benzyl,

R5 means hydroxy,

R7 means benzyl, and

the asymmetric carbon atoms carrying the residues R3 and R5 exist in S-configuration,

as well as pharmacologically acceptable salts of this compound,

or a compound of formula I, wherein

Ri and Rg mean the monovalent residue of the amino acid (L)-valine attached above the carboxy group, on the amino nitrogen atom with 4-thiomorpholinocarbonyl acsrled,

Ro, R4, Ra and Rg mean hydrogen,

R3 means benzyl,

R5 means hydroxy,

R7 means isobutyl,

and the asymmetric carbon atoms carrying the residues R3 and R5 exist in S-configuration,

as well as pharmacologically acceptable salts of this compound,

or a compound of formula I, wherein

R^ and Rg mean a monovalent residue of the amino acid (L)-valine bonded above the carboxy group and acylated on the amine nitrogen with benzyloxycarbonyl,

R 2 , R 4 , R 8 and R 8 mean hydrogen,

R3 means benzyl,

R5 means hydroxy,

R7 means p-cyanobenzyl,

and the asymmetric carbon atoms carrying the residues R3 and R5 exist in S configuration,

as well as pharmacologically acceptable salts of this compound,

or a compound of formula I, wherein

Ri and Rg mean the monovalent residue of the amino acid (L)-isoleukin bonded above the carboxy group, on the amino nitrogen atom with 4-thiomorpholinocarbonyl acylated,

R2, R4. R6 °S R8 means hydrogen,

R3 means benzyl,

R5 means hydroxy,

R7 means isobutyl,

and the asymmetric carbon atoms carrying the residues R3 and R5 exist in S configuration,

as well as pharmacologically acceptable salts of this compound.

The most preferred compounds are those mentioned in the examples and their salts.

The compounds of formula I and salts of such compounds with at least one salt-forming group are prepared in a manner known per se, for example by

a) adds a hydrazine derivative of the formula:

where the residues have the above meaning, on a

epoxy with the formula:

where the residues have the meaning stated above, whereby the free functional groups, with the exception of the groups participating in the 1 reaction, are possibly present in a protected form, and possibly clefts of the protective groups present or b) condenses an amlnocompound with the formula:

where the residues have the aforementioned meaning, with an acid with

the formula:

or a reactive acid derivative thereof, in which R9 has the aforementioned meaning, whereby the free functional groups with the exception of the 1 reaction participating groups possibly

is present in protected form, and leaves any protective groups present, or

c) condenses an amlno compound with the formula:

where the residues have the indicated meaning, with an acid with

the formula:

or reactive derivatives thereof, where Rj has the stated meaning, whereby the free functional groups, with the exception of the groups participating in the reaction, are possibly present in protected form, and clefts of any protective groups present, or d) for the preparation of compounds of formula I, where R^ and Rg mean two identical residues and the other residues have the indicated meaning, condenses a dlamlno compound with the formula:

where the residues have the indicated meaning, with an acid suitable for introducing the identical residues Rj and Rg or reactive acid derivatives thereof, in which R^ and Rg have the last indicated meaning, whereby the free functions

functional groups with the exception of the 1 groups participating in the reaction, possibly present in 1 protected form, and possibly gaps of protective groups present, or

e) 1 a compound of formula I<*>:

where R7' means hydrogen and the other residues have the above meaning, the residue R7 is introduced by substitution with a compound of formula:

where X means a leaving group and R 7 means lower alkyl;

cyclohexyl lower alkyl; or phenyl lower alkyl, which is unsubstituted or substituted with halogen, lower alkoxy or cyano, whereby the free functional groups, with the exception of those participating in the reaction, are possibly present in protected form, and possibly clefts of protective groups present, or

f) in a compound of formula I where the substituents R1-R9 have the above-mentioned meaning, provided that, in the

subject compound of formula I, at least one functional group is protected with a protecting group, clefts of protecting groups present, and

possibly transfer according to one of the steps a) to

f) obtained compound of formula I with at least one salt-forming group to the corresponding salt or transfers an obtained

salt to the free compound or to another salt,

and/or optionally separates obtained isomer mixtures, and/or converts one of the invention's compounds with formula I into another compound according to the invention with formula I.

The methods specified above shall be described in more detail below:

Method a) (addition of an amine to an epoxide):

The amlno group participating in the 1 reaction in the hydrazine water with formula III has, depending on the meaning of R7, preferably at least one free hydrogen atom; however, it can also itself be derivatized to increase the reactivity of the hydrazine derivative.

The epoxide of formula IV in particular has a structure which allows the terminal addition of the hydrazine water to take place as a preferred reaction.

Functional groups in starting materials whose conversion is to be avoided, especially carboxy, amino and hydroxy groups, can be protected with suitable protecting groups (conventional protecting groups), which are usually used in the synthesis of peptide compounds, but also of cephalosporins and penicillins as well as nucleic acid derivatives and sugars. These protective groups can already be present in the early stages and must protect the relevant functional groups against unwanted side reactions such as acylation, etherification and esterification, oxidation, solvolysis and so on. In special cases, the protective groups can, in addition to this, cause a selective, for example stereoselective turnover process. Characteristic of protective groups is that they can be easily split off, that is to say without unwanted blreactions, for example in a solvolytic, reductive, photolytic or also enzymatic way, for example also under physiological conditions. However, protecting group-analogous residues may also be present in the final products. Compounds of formula I with protected functional groups may exhibit a higher metabolic stability or otherwise improved pharmacodynamic properties than the corresponding compounds with free functional groups. In the above and in the following, it concerns protective groups in a narrower sense when the relevant residues are no longer present in the end products.

The protection of functional groups with such protecting groups, the protecting groups themselves as well as their cleavage reactions are described, for example, in standard works such as J.F.W. McOmle, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973, in Th.W. Green, "Protective Groups in Organic Synthesis", Wiley, New York 1981, in "The Peptides", Volume 3 (E. Gross and J. Meienhofer, eds.), Academic Press, London and New York 1981, in "The Method of organisenen Chemie", Houben-Weyl, 4th edition, volume 15/1, Georg Thieme Verlag, Stuttgart 1974, in H.-D. Jakubke and H. Jescheit, "Aminosauren, Peptide, Proteine", Verlag Chemie, Weinneim, Deerfield Beach and Basel 1982 and in Jochen Lehmann, "Chemie der Kohlenhydrate: Monosaccharlde und Derivate", Georg Thieme Verlag, Stuttgart 1974.

A carboxy group is, for example, protected as an ester group which can be selectively cleaved off under foaming conditions. A carboxy group protected in esterified form is primarily esterified with a lower alkyl group which is preferably branched in the 1-position in the lower alkyl group or in the 1- or 2-position in the lower alkyl group with suitable substituents.

A protected carboxy group which is esterified with a lower alkyl group is, for example, methoxycarbonyl or ethoxycarbonyl.

A protected carboxy group that is esterified with a lower alkyl group that is branched in the 1-position of the lower alkyl group is, for example, tert-lower carboxycarbonyl such as tert-butoxycarbonyl<y>l•

A protected carboxy group that is esterified with a lower alkyl group that is substituted in the 1- or 2-position of the lower alkyl group with suitable substituents is, for example, arylmethoxycarbonyl with one or two aryl residues, where aryl is unsubstituted or means with lower alkyl, for example tert-lower alkyl as tert -butyl; lower alkoxy, for example methoxy, hydroxy, halogen, for example chlorine and/or nitro mono-, di- or tri-substituted phenyl, for example benzyloxycarbonyl, for example 4-nitrobenzyloxycarbonyl or 4-methoxybenzyloxycarbonyl, diphenylmethoxycarbonyl or diphenylmethoxycarbonyl substituted with the aforementioned substituents, for e.g. di-(4-methoxyphenyl)-methoxycarbonyl, further with a lower alkyl group esterified carboxy, whereby the lower alkyl group is substituted in the 1- or 2-position with suitable substituents such as 1-lower alkyllower oxycarbonyl, for example methoxymethoxycarbonyl, 1-methoxyethoxycarbonyl or 1-ethoxyethoxycarbonyl, 1 -lower alkyllolavereal oxycarbonyl, for example 1-methylthiomethoxycarbonyl or 1-ethylthioethoxycarbonyl, aroylmethoxycarbonyl, in which the aroyl group is optionally, for example, with a halogen such as bromine, substituted benzoyl, for example phenacyloxycarbonyl, 2-halo lower realoxycarbonyl, for example 2,2,2-trichloroethoxycarbonyl, 2 -bromoethoxycarbon yl or 2-iodoethoxycarbonyl as well as 2-(trisubstituted silyl)-lower alkylcarbonyl, where the substituents independently each have an optionally, for example with lower alkyl, lower alkoxy, aryl, halogen and/or nitro substituted aliphatic, araliphatic, cycloaliphatic or aromatic hydrocarbon residue , for example optionally as above substituted lower alkyl, phenyl lower alkyl, cycloalkyl or phenyl, for example 2-trilower alkylsilyl lower alkyl oxycarbonyl such as 2-trilower alkylsilylethoxycarbonyl, for example 2-trimethylsilylethoxycarbonyl or 2-(di-n-butyl-methyl-silyl)-ethoxycarbonyl or 2 -triaryl-silylethoxycarbonyl such as triphenylsilylethoxycarbonyl.

A carboxy group can also be protected as organic silyloxycarbonyl groups. An organic silyloxycarbonyl group is, for example, a lower alkylsilyloxycarbonyl group, for example trimethylsilyloxycarbonyl. The silicon atom of the silyloxycarbonyl group can also be substituted with two lower alkyl groups, for example methyl groups, and the amino group or the carboxyl group 1 a second molecule with formula I. The compounds with such protective groups can be prepared, for example, with dimethylchlorosilane as the silylation solvent.

A protected carboxy group is preferably tert-lower oxycarbonyl, for example tert-butoxycarbonyl, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 9-fluorenylmethoxycarbonyl or diphenylmethoxycarbonyl.

A protected amino group can be protected with an amino-protecting group, for example in the form of an acylamino-, arylmethylamino-, etherified mercaptoamino-, 2-acyl-lower alk-1-enylamino- or sly1amino group or as an azido group.

In a corresponding acylamino group, acyl is for example the acyl residue of an organic carboxylic acid with, for example, up to 18 carbon atoms, in particular an optionally, for example with halogen or aryl substituted lower alkane carboxylic acid or optionally, for example with halogen, lower alkoxy or nitro, substituted benzoic acid, or preferably a carboxylic acid half-ester. Such acyl groups are, for example, lower alkyl such as formyl, acetyl, proplonyl or pivaloyl, halogen-lower alkanoyl, for example 2-haloacetyl such as 2-chloro-, 2-bromo-, 2-iodo-, 2,2,2-trifluoro- or 2 ,2,2-trichloroacetyl, optionally for example with halogen, lower alkoxy or nitro substituted benzoyl such as benzoyl, 4-chlorobenzoyl, 4-methoxy-benzoyl or 4-nitrobenzoyl, lower alkoxycarbonyl, preferably in the 1-position in the branched lower alkyl residue or in 1- or 2-position suitable substituted lower alkoxycarbonyl, for example tert-lower alkoxycarbonyl such as tert-butoxycarbonyl, arylmethoxycarbonyl with one, two or three aryl residues as optional, for example with lower alkyl and especially tert-lower alkyl as tert-butyl, lower alkoxy as methoxy, hydroxy, halogen as chlorine, and/or nitro mono- or polysubstituted phenyl, for example benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, diphenylmethoxycarbonyl, 9-fluorenylmethoxycarbonyl or di-(4-methoxyphenyl)-methoxycarbonyl, aroylmethoxycarbonyl, in which the aroyl group is preferably optionally with, for example, halogen such as bromine, substituted benzoyl, for example phenacyloxycarbonyl, 2-halo-1averealoxycarbonyl, for example 2,2,2-trichloroethoxycarbonyl, 2-bromomethoxycarbonyl or 2-iodoethoxycarbonyl, 2-(trisubstituted silyl )-lower oxycarbonyl, for example 2-tri-lower alkyl slylylave oxycarbonyl such as 2-trimethylsilylethoxycarbonyl or 2-(di-n-butyl-methyl-silyl)-ethoxycarbonyl such as triarylsilyl lower oxycarbonyl, for example 2-triphenylslylethoxycarbonyl.

In an arylmethylamino group which, for example, constitutes a mono-, di- or especially triarylmethylamino group, the aryl residues are especially optionally substituted phenyl residues. Such groups are, for example, benzyl, diphenylmethyl or especially tritylamino groups.

In an etherified mercaptoamino group, the mercapto group is primarily present as substituted arylthio or arylloweralkyl-thio, where aryl is, for example, optionally with, for example, loweralkyl such as methyl or tert-butyl, loweralkyl such as methoxy, halogen such as chlorine, and/or nitro, substituted phenyl, for example 4-nitrophenylthio.

In a 2-acyl-lower alk-1-enyl residue that can be used as an amino protecting group, acyl is, for example, the corresponding residue of a lower alkane carboxylic acid, one optionally with, for example, lower alkyl such as methyl or tert-butyl-1, lower alkoxy such as methoxy, halogen such as chlorine, and/ or nltro, substituted benzoic acid, or in particular a carboxylic acid half-ester such as a carboxylic acid-lower alkyl half-ester. Corresponding protecting groups are primarily l-lower alkanoyl-lower alk-l-en-2-yl, for example l-lower alkanoyl-prop-l-en-2-yl such as 1-acetyl-prop-l-en-2-yl or lower alkoxycarbonyl-lower alk-1-en-2-yl, for example lower alkoxycarbonyl-prop-1-en-2-yl such as 1-ethoxycarbonyl-prop-1-en-2-yl.

A silylamino group is, for example, a lower alkylsilylamino group such as trimethylsilylamino or tert-butyldimethylsilylamino. The syllium atom 1 in the sylylamino group can also be substituted only with two lower alkyl groups, for example methyl groups, and the amino group or the carboxyl group in a second molecule of formula I. Compounds with such protective groups can, for example, be prepared using the corresponding chloroslans such as dlmethylchloroslan as silylation agent.

An amino group can also be protected by transfer to the protonated form; As corresponding anions, those of strong inorganic acids such as sulfuric acid, phosphoric acid or hydrohalogenic acids, for example the chlorine or bromine anion, or of organic sulphonic acids such as p-toluenesulphonic acid come into consideration.

Preferred amino protecting groups are lower alkoxycarbonyl, phenyl lower alkyl, fluorenyl lower alkyl, 2-lower alkanoyl-lower alk-1-en-2-yl or lower alkoxycarbonyl-lower alk-1-en-2-yl.

A hydroxy group can, for example, be protected with an acyl group, for example with halogen such as chlorine, substituted lower alkanoyl such as 2,2-dichloroacetyl, or in particular with an acyl residue of a carboxylic acid half-ester mentioned for protected amino groups. A preferred hydroxy protecting group is, for example, 2,2,2-trichloroethoxycarbonyl, 4-nitrobenzyloxycarbonyl, diphenylmethoxycarbonyl or trityl. A hydroxy group can further be protected with tri-lower alkylsilyl, for example trimethylsilyl, triisopropylsilyl or tert-butyl-dimethylsilyl, an easily cleavable etheric group, for example an alkyl group such as tert-lower alkyl, for example tert-butyl, an oxa- or a thia-alphatic or -cyclo-allphatlic, and in particular 2-oxa- or 2-thialiphatic or -cycloaliphatic hydrocarbon residue, for example 1-lower-alkylloweralkyl or 1-loweralkyltloloweralkyl such as methoxymethyl, 1-methoxyethyl, 1-ethoxyethyl, methylthiomethyl, 1-methylthioethyl or 1 -ethyltloethyl or 2-oxa- or 2-tla-cycloalkyl with 5 to 7 ring atoms such as 2-tetrahydrofuryl or 2-tetrahydropyranyl or a corresponding thia analogue, as well as with 1-phenyllower alkyl such as benzyl, dlphenylmethyl or trityl, whereby the phenyl residue can for example be substituted with halogen such as chlorine, lower alkoxy such as methoxy, and/or nitro.

A neighboring pair of hydroxy and amino groups occurring in 1 molecule can, for example, be protected with divalent protecting groups such as a preferably, for example with one or two lower alkyl residues or oxo, substituted methylene group, for example with unsubstituted or substituted alkylidene, for example lower alkylidene which isopropylidene, cycloalkylidene such as cyclohexylidene, a carbonyl group or benzylidene.

As a protecting group, for example a carboxy protecting group, Within the spirit and framework of the invention, mention must also be made of an easily cleavable polymer support which is connected to the group, for example the carboxy group, to be protected, for example as they are suitable for the Merrifield synthesis. Such a suitable polymer carrier is, for example, a polystyrene resin weakly cross-linked by copolymerization with divinylbenzene, which carries bridge links that are suitable for reversible bonding.

The addition of the compounds of formula III to the epoxides of formula IV takes place preferably under the usual reaction conditions for the addition of nucleophiles to epoxides.

The addition takes place in particular in aqueous solution and/or in the presence of polar solvents such as alcohols, for example methanol, ethanol or ethylene glycol, ethers such as dioxane, amides such as dimethylformamide, or phenols such as phenol, also under anhydrous conditions, 1 apolar solutions such as benzene or toluene . 0<*>C to the corresponding reaction mixture's boiling temperature, preferably between 20<*>C and 130<*>C, possibly under reflux, under elevated pressure such as 1 bomb tube, whereby the boiling temperature can also be exceeded, and/or under lnert gas such as nitrogen or argon, whereby each of the two compounds with the formulas III and IV can be present in excess, for example in a molar ratio of 1:1 to 1:100, preferably 1:1 to 1:10 and most preferably 1: 1 to 1:3.

The release of the protected groups takes place according to the methods described under method f) (removal of protective groups).

Method b) (preparation of an amide bond):

In the starting materials in the formulas V and VI, functional groups, with the exception of groups which are to participate in the reaction or which do not react under the reaction conditions, are independently protected by one of the protective groups mentioned under method a).

The compounds of formula VI contain a free carboxy or sulfo group and reactive acid derivatives thereof, for example the derived activated esters or reactive anhydrides, further reactive cyclic amides. The reactive acid derivatives can also be formed in situ.

Activated esters of the compounds of formula Vi with end-to-end varhox variants are special now the compound carbon atom

1 the residue to be esterified unsaturated esters, for example of the woolen ester type such as woolen ester (obtainable for example by reacting a corresponding ester with vinyl acetate; the activated woolen ester method), carbamoyl esters (obtainable for example by treating the corresponding acid with an isoxazolum reagent; 1, 2-oxazolium or Woodward method), or 1-lower oxyvinyl ester (obtainable, for example, by treating the corresponding acid with a lower alkoxyacetylene; ethoxyacetylene method), or esters of the amldlno type such as N,N'-disubstituted amlnoester ( obtainable for example by treatment of the corresponding acid with a suitable N,N<*->disubstituted carbodilmid, for example N,N'-dicyclohexylcarbodillimide; the carbodilmid method), or N,N-disubstituted amldinoesters (obtainable for for example by treating the corresponding acid with an N,N-disubstituted cyanamide; the cyanamld method), suitable aryl esters, especially with electron-withdrawing substituents suitably substituted pheny esters (obtainable for example by treatment of the corresponding acid with a suitable substituted phenol, for example 4-nitrophenol, 4-methylsulfonylphenol, 2,4,5-trichlorophenol, 2,3,4,5,6-pentachlorophenol or 4-phenyldiazophenol , in the presence of a condensing agent such as (N,N'-dicyclohexylcarbodiimide; the activated aryl ester method) cyanomethyl ester (obtainable for example by treating the corresponding acid with chloroacetonitrile in the presence of a base; the cyanomethyl ester method), thioesters and in particular optionally for example with nitro substituted phenylthioester (obtainable for example by treating the corresponding acid with optionally, for example with nitro, substituted thiophenols, including by means of the anhydride or carbodilimld method; the method with the active thiol ester), or especially amino or amido esters (obtainable, for example, by treating the corresponding acid with a N -hydroxyamino- or N-hydroxyamido compound, for example N-hydroxysuccinimide, N-hydroxy-piperidine, N-hydroxyphthalimide, N-hydroxy-5-norbornene-2,3-dlcarboxylic acid lmld, 1-hydroxybenztriazole or 3-hydroxy-3, 4-dihydro-1,2,3-benztriazin-4-one, for example according to the anhydride or carbodilimld method; the activated N-hydroxyester method). One can also use internal esters, for example -y-lactones.

Anhydrides of acids can be symmetrical or preferably mixed anhydrides of these acids, for example anhydrides with inorganic acids such as acid halides and especially acid chlorides (obtainable for example by treating the corresponding acid with thlonyl chloride, phosphorus pentachloride, phosgene or oxalyl chloride; the acid chloride method), azides (obtainable for example from a corresponding acid ester via the corresponding hydrazld and its treatment with nitric acid; the azld method), anhydrides with carboxylic acid half-esters, for example carboxylic acid lower alkyl half-esters (obtainable for example by treating the corresponding acid with chloroformic acid lower alkyl esters or with a l-lower oxycarbonyl- 2-lower oxy-1,2-dihydroquinoline; the mixed 0-alkylcarboxylic acid anhydride method), or anhydrides with dihalogenated and especially dichlorinated phosphoric acids (obtainable, for example, by treating the corresponding acid with phosphoryl oxychloride; the phosphoric oxychloride method), anhydrides with other phosphoric acid derivatives vats (for example, such as can be obtained with phenyl-N-phenylphosphoramidochloridate or by reacting alkylphosphoric acid amides in the presence of sulfonic anhydrides and/or racemization-reducing additives such as N-hydroxy-benztrlazole, or in the presence of cyanophosphonic acid diethyl esters) or with phosphoric acid derivatives or anhydrides with organic acids as mixed anhydrides with organic carboxylic acids (obtainable, for example, by treating the corresponding acid with an optionally substituted lower alkane or phenyl lower alkane carboxylic acid halide, for example phenylacetic, pivalinic or trifluoroacetic acid chloride; the method with mixed carboxylic acid anhydrides)*or with organic sulphonic acids (obtainable, for example, by treating a salt, for example an alkali metal salt, of the corresponding acid with a suitable sulphonic acid halide such as lower alkane- or arvl-. for exenmel methane- or D-toluenesulfonic chloride: method with mixed sulphonic acid anhydrides) as well as symmetrical anhydrides (obtainable, for example, by condensation of the corresponding acid in the presence of a carbodiimide or of a dlethylamnolpropln; the method with symmetrical anhydrides).

Suitable cyclic amides are in particular amides with 5-membered dlazacycles of the aromatic type such as amides with imidazoles, for example imidazole (obtainable for example by treating the corresponding acid with N,N'-carbonyldilimidazole; the imidazole method), or pyrazole, for example 3,5-dimethylpyrazole (obtainable, for example, via the acid hydrazide by treatment with acetylacetone; the pyrazolid method).

As mentioned, derivatives of carboxylic acids that are used as acylating agents can also be formed in situ. Thus, for example, N,N'-disubstituted amidinoesters can be formed in situ by reacting the mixture of the starting material with formula V and the acid used as acylating agent in the presence of a suitable N,N'-disubstituted carbodiimide, for example N,N '-cyclohexylcarbodiimide. Furthermore, amino or amido esters of the acids used as acylating agents can be formed in the presence of the starting material of formula V to be acylated, reacting the mixture of the corresponding acid and amino starting materials in the presence of an N,N'-disubstituted carbodiimide, for example N,N'-dicyclohexylcarbodiimide and an N-hydroxyamine or N-hydroxyamide, for example N-hydroxysuccinimide, optionally in the presence of a suitable base such as 4-dimethylaminopyridine. Furthermore, by reaction with N,N,N<*>,N'-tetraalkyluronium compounds such as O-benztriazol-1-yl-N,N,N',-tetramethyl-uronium-hexafluorophosphate, 0-(1,2-dihydro -2-oxo-1-pyridyl)-N,N,N',N'-tetramethyluronium tetrafluoroborate or O-(3,4-dihydro-4-oxo-1,2,3-benz-triazolin-3-yl )-N,N,N',N'-tetramethyluronium tetrafluoroborate achieve activation in situ. Finally, phosphoric anhydrides of the carboxylic acids of formulas Vi and VII can be prepared in situ by reacting an alkylphosphoric acid amide such as hexamethylphosphoric acid triamide in the presence of a sulfonic acid anhydride such as 4-toluenesulfonic acid anhydride with a salt such as a tetrafluoroborate, for example sodium tetrafluoroborate, or with another derivative of hexamethylphosphoric acid triamide such as benzotriazol-1-yl-oxy-tris-(dlmethylamino)-phosphonium hexafluoride, preferably in the presence of a racemization-decreasing additive such as N-hydroxybenztriazole.

In an analogous manner, several of the reaction types specified above for carboxylic acid with formula VI can also be carried out for compounds with formula III with a terminal sulfonyl group by condensation with compounds with formula V to form sulfonamides.

Thus, for example, activated sulfonic acid esters can be used, for example the corresponding and particularly nitro-group substituted aryl esters such as phenyl ester, whereby the amine component of formula V can also be used as an alkali metal amide, for example an alkali metal aryl amide such as sodium anlllnamld, or an alkali metal salt of Nitrogen-containing heterocycles such as potassium pyrrolide.

Furthermore, one can use reactive anhydrides such as, for example, the corresponding symmetrical ones (producible, for example, by reacting the alkylsulfonic acid silver salts with alkylsulfonyl chlorides) or preferably asymmetric acid chlorides, for example, anhydrides with inorganic acids such as sulfonyl halides and especially sulfonyl chlorides (obtainable, for example, by reacting the corresponding sulfonic acids with inorganic acid chlorides such as thionyl chloride, phosphorus pentachloride), with organic carboxylic acids (obtainable, for example, by treating a sulfonic acid halide with the salt of a carboxylic acid as an alkali metal salt, analogous to the above-mentioned method with mixed sulfonic anhydrides)\ or azlder (obtainable, for example, from the corresponding sulfone -acid chloride and sodium azide or via corresponding hydrazide and its treatment with nitric acid analogously to the azide method indicated above).

The amino group of formula V which participates in the reaction preferably carries at least one reactive hydrogen atom, particularly when the thus reacting carboxy, sulfonyl or phosphoryl group is present in a reactive form; however, they can also themselves be derivatized, for example by reaction with a phosphite such as diethyl chlorophosphite, 1,2-phenylene chlorophosphite, ethyl dichlorophosphite, ethylene chlorophosphite or tetraethyl pyrophosphite. A derivative of such a compound with an amino group is, for example, also a carbamlnic acid chloride or an isocyanate, whereby the amino group participating in the reaction is, for example, substituted with halocarbonyl as a chlorocarbonyl or converted as an isocyanate group, whereby in the latter case only compounds of the formula are available I as on the nitrogen atom 1 the amld group formed by the reaction carries a hydrogen atom.

The condensation to produce an amide mixture can take place in a manner known per se, for example as described in standard works such as "Houben-Weyl, Methoden der organischen Chemie", 4th edition, volume 15/11 (1974), volume IX (1955 ), Volume E 11 (1985), Georg Thieme Verlag, Stuttgart, "The Peptides" (E. Gross and J. Neienhofer, Eg.), Volumes 1 and 2, Academlc Press, London and New York, 1979/1980, or M. Bodansky, "Principles of Peptide Synthesis", Springer Verlag, Berlin 1984.

The condensation of a free carboxylic acid with a corresponding amine can preferably be carried out in the presence of one of the usual condensation agents or using carboxylic acid anhydrides or halides such as chlorides, or activated carboxylic acid esters such as p-nitrophenyl esters. Common condensation agents are, for example, carbodiimides such as diethyl-, dipropyl-, N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide or especially dicyclohexylcarbodiimide, further suitable carbonyl compounds such as carbonylimidazole, 1,2-oxazolium compounds, for example 2-ethyl -5-phenyl-1,2-oxazolium-3'-sulfonate and 2-tert-butyl-5-methylisoxazolium perchlorate or a suitable acylamino compound such as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, N,N, N',N'-tetraalkyl-uronium compounds such as O-benztrlazol-1-yl-N,N,N'.N'-tetra-methyluronium hexafluorophosphate, further activated phosphoric acid derivatives, for example diphenylphosphoryl azide, diethylphosphoryl cyanide, phenyl-N- phenylphosphoroamidochloridate, bis-(2-oxo-3-oxazolidinyl)-phosphinic acid chloride or 1-benztriazolyloxy-tris-(dimethylamino)-phosphonium hexafluorophosphate.

Optionally, one adds an organic base, preferably a tertiary amine, for example a lower alkylamine with bulky residues, for example ethyl dlisopropylamine or triethylamine, and/or a heterocyclic base such as 4-dimethylaminopyridine or preferably N-methylmorpholine or pyridine.

The condensation of activated esters, reactive anhydrides or reactive cyclic amides with the corresponding amines is usually carried out in the presence of an organic base, for example simple trilower alkylamines such as triethylamine or tributylamine, or one of the above-mentioned organic bases. Optionally, one additionally uses a condensation agent as described for free carboxylic acids.

The condensation of acid anhydrides with amines can, for example, take place in the presence of inorganic carbonates such as ammonium or alkali metal carbonates or hydrogen carbonates such as sodium or potassium carbonate or hydrogen carbonate (if desired together with a sulfate).

Carboxylic acid chlorides, for example the chlorocarbonic acid derivatives derived from the acid with formula VI, or sulphonic acid chlorides, are condensed with the corresponding amines preferably in the presence of an organic amine, for example the above-mentioned lower alkylamine or heterocyclic bases, optionally in the presence of a hydrogen sulphate.

The condensation is preferably carried out in an inert, aprotic, preferably anhydrous solvent or a mixture thereof, for example 1 a carboxylic acid amide such as formaldehyde or dimethylformamide, a halogenated hydrocarbon such as methylene chloride, carbon tetrachloride or chlorobenzene, a ketone such as acetone, a cyclic ether such as tetrahydrofuran, a ester such as acetic acid ethyl ester or a nitrile such as acetonitrile, or in a mixture thereof, optionally at a lower or higher temperature, for example in a temperature range from approx. -40'C to +100<*>C and preferably from -10*C to +50<*>C, in the case of arylsulfonyl esters also at approx. +100°C to +200<*>C and possibly under an inert gas atmosphere, for example nitrogen or argon.

Also aqueous and mostly alcoholic, for example ethanol, or aromatic solvents, for example benzene or toluene, are possible. In the presence of alkali hydroxides as bases, acetone can optionally also be added.

The condensation can also be carried out according to the technique known as solid-phase synthesis, which goes back to R. Merrifield and which is described, for example, in "Angew. Chem.", 97. 801-812 (1985), "Naturvissenschaften", 71 , 252-258 (1984) or in R.A. Houghten, "Proe. Nati. Acad. Sei.", USA 82, 5131-5136 (1985).

Depending on the starting compounds used, the residues R^ and Rg in the obtainable compounds of formula I can be identical or different from each other.

Release of protected groups takes place according to the methods described below under method f) (removal of protective groups).

Process c) (preparation of an amide bond)

In the starting materials with the formulas VII and VIII, functional groups, with the exception of groups which are to participate in the reaction or which do not react under the reaction conditions, are independently protected with one of the protective groups mentioned under method a).

The procedure is completely analogous to those mentioned under procedure b), when 1 instead of compounds of formula V, compounds of formula VII are used and instead of

compounds of formula VI use those of formula VIII and in the acylation use Rj instead of Rg on. compounds of formula VII instead of compounds of formula V.

Depending on the starting compounds used, the residues R^ and Rg in the obtainable compounds of formula I may be the same or different from each other.

The release of protected groups may take place according to the methods described below under procedure f) (removal of protective groups).

Method d) (preparation of an amide bond)

In the starting materials of formula IX and the acids suitable for the introduction of the identical residues R^ and Rg or their reactive derivatives, functional groups which are not to participate in the reaction or which do not react under the reaction conditions are independently protected by one of the a) said protective groups.

The acid suitable for introducing the identical residues R^ and Rg preferably has one of the formulas VI or VIII.

Preferably, starting compounds of formula IX, optionally protected with protective groups, are those of formula II as described under the section on the starting compounds.

The method is completely analogous to those mentioned under method b), whereby 1 instead of compounds of formula V those of formula IX are used and 1 instead of compounds of formula VI those of formulas VI or VIII are used.

The release of protected groups may take place according to the methods described below under method f) (removal of protective groups).

Method e) (alkylation of a secondary nitrogen atom)

In the starting materials of formula I' and the compounds of formula XII suitable for the introduction of the residues R7 or their reactive derivatives, functional groups which are not to participate in the reaction or which do not react under the reaction conditions are protected independently of each other by one of the methods a) said protective groups.

A cleavable group X is in particular a nucleofuge cleavable group which is selected from hydroxy esterified with strong organic or inorganic acids, such as with a mineral acid, for example hydrohalic acid such as hydrochloric acid, hydrobromic or hydroiodic acid, or with a strong organic acid such as an optionally with halogen as fluorine-substituted lower alkanesulfonic acid or an aromatic sulfonic acid, for example a benzenesulfonic acid optionally substituted with lower alkyl such as methyl, halogen such as bromine and/or nitro, for example a methanesulfonic, p-bromotoluenesulfonic acid or p-toluenesulfonic acid esterified hydroxy or with nitrogen hydrogen acid esterified hydroxy .

The substitution can take place under the conditions of a nucleophilic substitution of the first or second degree.

For example, one can insert one of the compounds of formula XII where X means a cleavable group with high polarizability in the electron shell, for example iodine, in a polar, aprotic solvent such as acetone, acetonitrile, nitromethane, dimethylsulfoxide or dimethylformamide. The reaction can also be carried out in water to which, if necessary, an organic solvent, for example ethanol, tetrahydrofuran or acetone, has been added as a solvent. The substitution reaction is optionally carried out at a lower or higher temperature, for example within a temperature range from -40 °C to approx. +100'C, preferably approx. -10°C to approx.. +50<*>C and optionally under inert gas, for example under a nitrogen or argon atmosphere.

The release of protected groups may take place according to the methods described below under procedure f) (removal of protective groups).

Method f) (removal of protective groups)

Removal of the protective groups which are not a component of the desired end product with formula I, for example the carboxy, amino and/or hydroxy protecting groups, takes place in a manner known per se, for example by solvolysis and especially hydrolysis, alcoholysis or azldolysis, or by means of reduction, in particular hydrogenolysis or chemical reduction, as well as photolysis, possibly stepwise or simultaneously, whereby enzymatic methods can also be used. The separation of the protection groups is described, for example, in the standard works mentioned earlier in the section "Protection groups".

Thus, for example, protected carboxy, for example tert-lower oxycarbonyl, in the 2-position with a trisubstituted silyl group or the 1 1-position with lower alkoxy or lower alkyl, can be substituted by lower alkoxycarbonyl or optionally substituted diphenylmethoxycarbonyl by treatment with a suitable acid such as formic acid, hydrochloric acid or trifluoroacetic acid , optionally with the addition of a nucleophilic compound such as phenol or anisole, is transferred to free carboxy. From lower alkoxycarbonyl, carboxy can also be set free with the help of bases such as hydroxides, for example alkali metal hydroxides such as NaOH or KOH. Optionally substituted benzyloxycarbonyl can, for example, be set free by means of hydrolysis, that is to say treatment with hydrogen in the presence of metallic hydrogenation catalysts such as a palladium catalyst. Furthermore, suitable substituted benzyloxycarbonyl such as 4-nitrobenzyloxycarbonyl can, also by reduction, for example by treatment with an alkali metal such as sodium dithionite or with a reducing metal, for example zinc or a reducing metal salt such as a chromium(II) salt, for example chromium( II) chloride, usually in the presence of a hydrogen-releasing agent which together with the metal can form nascent hydrogen, as an acid, firstly a suitable carboxylic acid such as an optionally hydroxy-substituted lower alkane carboxylic acid such as acetic, formic, glycol, diphenylglycol, lactic, mandelic, 4-chloromandelic or tartaric acid or an alcohol or thiol, whereby water is preferably added, is transferred to free carboxy. By treatment with a reducing metal or metal salt as described above, 2-halo-lower oxycarbonyl (possibly after conversion of a 2-bromo-lower oxycarbonyl group to a corresponding 2-iodo-lower alkoxycarbonyl group) or aroylmethoxycarbonyl can also be converted to free carboxyl. Aroylmethoxycarbonyl can likewise be cleaved by treatment with a nucleophilic, preferably salt-forming reagent such as sodium thiophenolate or sodium iodide. 2-(trisubstituted silyl)-lower alkyl carbonyl such as 2-trilower alkylsilyl lower carboxycarbonyl can be converted to free carboxyl by treatment with a salt of hydrofluoric acid which gives a fluoride anion, for example an alkali metal fluoride such as sodium or potassium fluoride, optionally in the presence of a macrocyclic polyether ("crown- ether") or with a fluoride of an organic quaternary base such as tetralower alkylammonium fluoride or lower alkylaryllower alkylammonium fluoride, for example tetraethylammonium fluoride or tetrabutylammonium fluoride, in the presence of an aprotic, polar solvent such as dimethyl sulfoxide or N,N-dimethylacetamide. As organic silyloxycarbonyl such as trilower alkylsilyloxycarbonyl, for example trimethylsilyloxycarbonyl, protected carboxy, can be set free in the usual way as described above solvolytically, for example by treatment with water, an alcohol or acid, or additionally fluoride. Esterified carboxy can also be set free enzymatically, for example with esterases or suitable peptidases, for example esterified arglnln or lysln as lysine methyl ester, with the help of trypsin.

A protected amino group is set free in a known manner and depending on the type of protecting group in different ways, preferably by means of solvolysis or reduction. Lower oxycarbonylamino such as tert-butoxycarbonylamino can be cleaved in the presence of acids, for example mineral acids such as hydrogen halides such as hydrogen chloride or hydrogen bromide, or with sulfuric or phosphoric acid, preferably hydrogen chloride, or by strong organic acids such as trihaloacetic acid, for example trifluoroacetic acid, or formic acid, in polar solvents such as water, or ethers, preferably cyclic ethers such as dloxane, 2-halo-lower oxycarbonylamino (possibly during the conversion of a 2-bromo-1-lower oxycarbonylamino group to a 2-iodolower oxycarbonyl group) or directly dissolved in a liquid organic carboxylic acid such as formic acid, aroylmethoxycarbonylamino or 4-nitrobenzyloxycarbonylamino can for example be cleaved by treatment with a suitable reducing agent such as zinc in the presence of a suitable carboxylic acid such as aqueous acetic acid. Aroylmethoxycarbonylamino can also be cleaved by treatment with a nucleophilic, preferably salt-forming reagent such as sodium thiophenolate, and 4-nitrobenzyloxycarbonylamino also by treatment with an alkali metal, for example sodium dithionite. Optionally substituted diphenylmethoxycarbonylamino, tert-lower alkylcarbonylamino or 2-(trisubstituted silyl)-lower alkylcarbonylamino such as 2-trilower alkylsilyllower alkoxycarbonylamino can be set free by treatment with a suitable acid, for example formic or trifluoroacetic acid, optionally substituted benzyloxycarbonylamino, for example by means of hydrogenolysis , that is, treatment with hydrogen in the presence of a suitable hydrogenation catalyst such as a platinum or palladium catalyst, optionally substituted triarylmethylamino or formylamino, for example by treatment with an acid such as mineral acid, for example hydrochloric acid, or an organic acid, for example formic -, acetic or trifluoroacetic acid, optionally in the presence of water, and a slylamlno protected amino group, for example by means of hydrolysis or alcoholysis. An amino group protected with 2-haloacetyl, for example 2-chloroacetyl, can be set free by treatment with thiourea in the presence of a base, or with a tluolate salt, such as an alkali metal tluolate of thiourea, and then subsequent solvolysis such as alcoholysis or hydrolysis, of the obtained substitution product, from trifluoroacetylamino the amino is set free, for example by hydrogenolysis with bases such as alkali metal hydroxides or carbonates, such as Na£C03 or K2CO3, 1 polar solvents, for example alcohols such as methanol, at temperatures between 0 and 100°C and in particular at 40' C to 80"C. An amino group protected with 2-(trisubstituted silyl)-lower carboxycarbonyl such as 2-trilower alkylsilyl lower oxycarbonyl can also be transferred by treatment with a fluoroldanlon-forming salt of hydrofluoric acid as described above in connection with the release of a corresponding protected carboxy group, to the free amino group Likewise, with the help of fluorine ions, silyl can be cleaved such as trimethylsilyl which is b directly to a heteroatom such as nitrogen.

In the form of an azido group protected amino is transferred, for example, by reduction to free amino, for example by catalytic hydrogenation with hydrogen in the presence of a hydrogenation catalyst such as platinum oxide, palladium or Rajiey nickel, by reduction by means of mercapto compounds such as dithiothreltol or mercaptoethanol, or also by treatment with zinc 1 in the presence of an acid such as acetic acid. The catalytic hydrogenation is preferably carried out in an inert solvent such as a halogenated hydrocarbon, for example methylene chloride, or also 1 water or a mixture of water and an organic solvent such as an alcohol or dioxane, at 20<*>C to 25<*> C or also during cooling or heating.

A protected hydroxy group with a suitable acyl group, a trilower alkylsilyl group or optionally substituted 1-phenyllower alkyl is set free analogously to a corresponding protected amino group. A hydroxy group protected with 2,2-dichloroacetyl is set free, for example, by basic hydrolysis, a hydroxy or mercapto group protected with a tert-lower alkyl or with a 2-oxa- or 2-thia-aliphatic or -cycloaliphatic hydrocarbon residue is set free by azidolysis, for for example by treatment with a mineral acid or a strong carboxylic acid, for example trifluoroacetic acid. Neighboring amino and hydroxy groups which are together protected by means of a bivalent protecting group, preferably for example a methylene group substituted with lower alkyl once or twice, which with lower alkylidene, for example isopropylidene, cycloalkylidene, for example cyclohexylidene, or benzylidene, can be set free by acid solvolysis, especially in the presence of mineral acid or a strong organic acid. A trilower alkylsilyl group is likewise split off by azidolysis, for example with mineral acid and preferably hydrofluoric acid, or a strong carboxylic acid. 2-halogen lower oxycarbonyl is removed by means of the above-mentioned reducing agents, for example reducing metal such as zinc, reducing metal salts such as chromium (II) salts or with sulfur compounds, for example sodium dithlonite or preferably sodium sulphide and carbon sulphide.

In the presence of several protected functional groups, if desired, the protecting groups can be selected so that more than one such group can be cleaved off at the same time, for example azldolytically, as by treatment with trifluoroacetic acid, or with hydrogen and a hydrogenation catalyst such as a palladium-carbon catalyst. Conversely, the groups can also be selected so that not all of them are cleaved off at the same time, but are cleaved off in the desired order, whereby the corresponding intermediate products are obtained.

Additional precautions

In the case of the additional precautions that may be implemented if desired, functional groups of the starting compounds which are not to participate in the reaction may be present unprotected or in protected form, for example by one or more of the protective groups mentioned above under procedure a). The protective groups can remain in the final products or be split off in whole or in part according to one of the methods mentioned under procedure f).

Salts of compounds of formula I can be prepared with at least one salt-forming group in a manner known per se. Thus, one can form salts of compounds of formula I with acidic groups, for example by treatment with metal compounds such as alkali metal salts of suitable organic carboxylic acids, for example the sodium salt of 2-ethylhexanoic acid, with organic alkali or alkaline earth metal compounds such as the corresponding hydroxides, carbonates or bicarbonates such as sodium -and potassium hydroxide, -carbonate or -hydrogencarbonate, with corresponding calcium compounds or with ammonia, or a suitable organic amine, preferably using stoichiometric amounts or only a small excess of the salt-forming agent. Acid addition salts of the compounds of formula I are obtained in the usual way, for example by treatment with an acid or with a suitable ion exchanger. Inner salts of the compounds of formula I which contain acidic and basic salt-forming groups, for example a free carboxy group and a free amino group, can be formed, for example, by neutralizing salts such as acid addition salts at the isoelectric point, for example with weak bases, or by treatment with wage-changers.

Salts can be transferred in the usual way to the free compounds, metal and ammonium salts, for example, by treatment with suitable acids, and acid addition salts, for example, by treatment with a suitable basic agent.

Stereoisomeric mixtures, i.e. mixtures of diastereomers and/or enantiomers such as racemic mixtures, can be separated in a manner known per se by suitable separation methods into the corresponding isomers. Thus, diastereomer mixtures can be separated by fractional crystallization, chromatography, solvent partitioning, and so on into the individual diastereomers. Racemates can be separated after transfer of the optical antipodes to diastereomers, for example by reaction with optically active compounds, for example optically active acids and bases, by chromatography with optically active compounds coated column materials or by enzymatic methods, for example by selective reaction of only one of the two enantiomers. This separation can take place both in the case of starting products and in the case of compounds of formula I themselves.

At certain chirality centers in a compound of formula I, the configuration can be purposefully reversed. For example, one can reverse the configuration of asymmetric carbon atoms that carry nucleophilic substituents such as amino- or hydroxy, by nucleophilic substitution of a different order, possibly after transfer of the bound nucleophilic substituents to a suitable nucleofuge leaving group and reaction with a reagent that introduces the original substituent, or one can reverse the configuration of carbon atoms with hydroxy groups such as carbon atoms in formula I bearing R5, by oxidation and reduction of compounds of formula I as described below.

The residues hydroxy R5 and hydrogen Rg in a compound of formula I can be oxidized to an oxo group, whereby such oxidizing agents are preferably used which selectively convert the hydroxy group into a keto group, for example chromic acid or derivatives thereof such as pyridinelum chromate or tert-butyl chromate, dichromate/sulphuric acid, sulfur trioxide in the presence of heterocyclic bases such as pyridine/SO3, further nitric acid, sulphurous or selenium oxide, or dimethylsulfoxide 1 the presence of oxalyl chloride, in water, aqueous or organic solvents such as halogenated solvents, for example methylene chloride, carboxylic acid amides such as dimethylformamide, or dilute alkylsulfoxides such as dimethylsulfoxide, in presence or absence of basic amines, for example trilower alkylamines such as triethylamine, at temperatures between -50"C and +100<*>C, preferably at -10°C to +50<*>C, for example as described in EP-Å -0 236 734.

Then, in the thus obtained compounds of formula I, where R5 and Rg together form an oxo group, this oxo group can be reduced to a hydroxy group. For the reduction of the oxo group 1 of a compound of formula I, reducing agents are suitable which, under the reaction conditions of the method, selectively or more quickly reduce an isolated keto group than amide groups that are present in the compounds of formula I.

In the first place, mention should be made here of suitable borohydrides such as alkali metal borohydrides, in particular sodium borohydride, lithium borohydride or sodium cyanoborohydride, further zinc borohydride or suitable aluminum hydrides such as alkali metal low-area oxy-aluminum hydride with bulky residues, for example lithium-tris-tert-butoxyaluminium hydride.

The reduction can also take place with hydrogen 1 in the presence of suitable heavy metal catalysts, for example Raney nickel or platinum or palladium catalysts, for example platinum or palladium activated carbon, or 1 according to Meerwein-Ponndorf-Verley with the help of aluminum alkanolates, especially aluminium-2 -propanolate or -ethanolate.

The reduction can preferably be carried out with stochlometric quantities or a reasonably measured excess of the reducing agent 1 an inert solvent at temperatures between -80°C and the boiling point of the solvent, for example between -20*C and +100<*>C, if necessary under protective gas , for example nitrogen or argon. An excess of the reducing agent is particularly necessary when this also reacts with the solvent, for example the protons 1 a protic solvent.

When using sodium borohydride, polar, protic solvents are suitable, for example methanol, ethanol or isopropanol; when using the other reducing agents, polar, aprotic solvents, for example tetrahydrofuran, are suitable.

In a compound of formula I, where Rj and Rg do not contain any aryl residues or not very active aryl residues, a phenyl residue present in R7 and/or R3 can be hydrogenated, for example by catalytic hydrogenation, particularly in the presence of heavy metal oxides such as rhodium/platinum mixed oxides, for example with the Nishlmura catalyst, preferably in a polar solvent such as an alcohol, for example methanol or ethanol, at temperatures between 0<*>C and 80'C, in particular between 10*C and 40<*>C, and at a hydrogen pressure of 1 to 10 atmospheres, for example at normal pressure.

In a compound of formula I, a present free amino group can be acylated, for example for the introduction of one of the residues mentioned for Ri or Rg in the definition of compounds of formula I. The acylation takes place according to the above under methods b), c) or d) for the condensation or one of the methods mentioned for the protecting groups or for example 1 according to one of those in "Organikum", 17th edition, VEB Deutscher Verlag der Wissen -schaften, Berlin (East) 1988, mentioned methods.

All of the above-mentioned methods can be carried out under known per se and preferably the specifically mentioned reaction conditions, in the absence or usually the presence of solvents or diluents, preferably those which are inert to the reagents used and dissolve them, in the absence or presence of catalysts, condensation agents or neutralizing reagents, for example ion exchangers such as cation exchangers, for example in H+<-> form, depending on the type of reaction and/or reaction participant at reduced, normal or elevated temperature, for example in the temperature range from approx. -100'C to approx. 190<*>C, preferably at approx. -80*C to approx. 150°C, for example at -80°C to -60°C, at room temperature, at -20°C to +40°C or at the boiling point of the solvent used, under atmospheric pressure or in a closed container, optionally under pressure and/or in an inert atmosphere, for example under an argon or nitrogen atmosphere.

In all starting and intermediate compounds, if salt-forming groups are present, salts may be present. Salts can also be present during the reaction of such compounds as long as the reaction is not disturbed.

At all reaction steps, isomer mixtures present can be separated into the individual isomers, for example diastereomers or enantiomers, or into any mixtures of isomers, for example racemates or diastereomer mixtures, for example analogously to the methods described under "further process conditions".

In special cases, for example during hydration, it is possible to achieve stereoselective reactions so that an easy attainment of individual isomers is possible.

For the solvents from which the suitable ones are selected for each reaction, mention must be made, for example, of water, esters such as lower alkyl or lower alkanols, for example acetic acid diethyl ester, ethers such as aliphatic ethers, for example dlethyl ether, or cyclic ethers such as tetrahydrofuran, liquid aromatic hydrocarbons such as benzene or toluene, alcohols such as methanol, ethanol or 1- or 2-propanol, nitriles such as acetonitrile, halogenated hydrocarbons such as methylene chloride, acid amides such as dlmethylformamide, bases such as heterocyclic nitrogen bases, for example pyridine, carboxylic acid anhydrides such as lower alkane anhydrides, such as acetic anhydride, cyclic, linear or branched hydrocarbons such as cyclohexane, hexane or isopentane, or mixtures of these solvents, for example aqueous solvents, as far as the description of the method does not indicate otherwise. Such solvents can also be used in processing, for example in chromatographs! or distribution.

The invention also relates to the embodiments of the process in which one starts from a compound obtained as an intermediate at any step and carries out the missing steps, or interrupts the process at any step or forms a starting material under the reaction conditions and uses it in the form of a reactive derivative or a salt, or obtains a compound obtainable according to the method of the invention under the reaction conditions and further processes this in situ. Thereby, one preferably starts from such starting materials which lead to the compounds indicated above as preferred, in particular as particularly preferred, primarily preferred and/or most preferred.

Pharmacist in spoon preparations:

The invention also relates to pharmaceutical preparations containing compounds of formula I.

The pharmacologically usable compounds according to the present invention can, for example, be used for the production of pharmaceutical preparations containing an effective amount of the active ingredient together with or a mixture with a significant amount of inorganic or organic, solid or liquid, pharmaceutically usable carriers.

The invention also includes a pharmaceutical preparation which is suitable for administration to warm-blooded animals, especially humans, for the treatment or inhibition of a disease which is due to an inhibition of a retroviral protease, in particular a retroviral aspartate protease such as HIV-I or HIV-II gag protease, for example a retroviral disease such as AIDS, comprising an effective amount for inhibiting the retroviral protease of a compound of formula I or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier.

The pharmaceutical preparations of the invention are those for enteral such as nasal, rectal or oral, or parenteral such as intramuscular or intravenous administration to warm-blooded animals (humans and animals), which contain an effective dose of the pharmacologically active ingredient alone or together with a significant amount of a pharmaceutically acceptable carrier. The dosage of the active ingredient depends on the species, body weight, age and the individual condition, individual pharmacokinetic factors, the disease to be treated and the intended method of application.

The compounds of the invention are used in the treatment of virally, particularly retrovirally caused diseases, for example AIDS, in that a therapeutically effective amount of the compounds of the invention with formula I is administered to a warm-blooded animal, for example humans, which needs such treatment due to one of the aforementioned diseases and especially AIDS. The doses, for example for people with a body weight of approx. 70 kg, lies between approx. 3 mg and 3 g, preferably between approx. 10 mg and 1.5 g, for example at approx. 300 to 1000 mg per person and day, preferably divided into 1 to 3 individual doses which can, for example, be the same size. Children usually receive half the adult dose.

The pharmaceutical preparations contain approx. 1 to 95*, and preferably 20 to 90* active ingredient. Pharmaceutical preparations according to the invention may for example be available in unit dose form as ampoules or the like, suppositories, dragées, tablets or capsules.

The pharmaceutical preparations according to the present invention are prepared according to methods known per se, for example by means of conventional dissolution, lyophilisation, mixing, granulation or coating methods.

Solutions of the active ingredients are preferably used, but in addition also suspensions and especially isotonic, aqueous solutions or suspensions whereby these can be prepared before use, for example in lyophilized preparations containing the active ingredient alone or together with a carrier such as mannitol. The pharmaceutical preparations may be sterilized and/or contain excipients such as preservatives, stabilisers, wetting and/or emulsifying agents, dissolution agents, salts for regulating the osmotic pressure and/or buffers, and are produced according to methods known per se , for example using conventional dissolution or lyophilization methods. The aforementioned solutions or suspensions may contain viscosity-increasing substances such as sodium carboxymethylcellulose, carboxymethylcellulose, dextran, polyvinylpyrrolidone or gelatin.

Suspensions 1 oil contains as an oil component the usual vegetable, synthetic or semi-synthetic oils for injection purposes. As such, special mention should be made of liquid fatty acid esters which, as an acid component, contain a long-chain fatty acid with 8 to 22, and especially 12 to 22 carbon atoms, such as lauric, tridecyl, myristic, pentadecyl, palmitic, margarine, stearin -, arachidic or behenic acid or similar unsaturated acids such as oleic, elaidic, erucic, brasidic or linoleic acid, possibly with the addition of antioxidants such as vitamin E, 3-carotin or 3,5-di-tert-butyl- 4-Hydroxytoluene. The alcohol component in these fatty acid esters has a maximum of 6 carbon atoms and is monohydric or polyhydric, for example monohydric, dihydric or trihydric alcohol such as methanol, ethanol, propanol, butanol or pentanol or isomers thereof, above all, however, glycol or glycerol. As fatty acid esters, ethyl oleate, isopropyl myristate, isopropyl palmitate, "Labrafil M 2375" should be mentioned

(polyoxyethylene glycerol trioleate from the company Gattefossé, Paris), "Miglyol 812" (triglyceride of saturated fatty acids with chain length Cg to C^ from the company Htlls AG, Germany), especially, however, vegetable oils such as cottonseed, almond, olive, castor- , sesame or soybean oil and above all peanut oil.

The production of the injection preparations takes place in the usual way under sterile conditions, as well as the filling in ampoules or similar and closing in containers.

Pharmaceutical preparations for oral use can be obtained by combining the active ingredient with solid carriers, possibly granulating an obtained mixture and, if desired or necessary, processing the mixture after adding suitable excipients into tablets, dragee cores or capsules. Thereby, they can be built into plastic carriers that release the active ingredient in a dosed manner or allow it to diffuse.

Suitable carriers are in particular fillers such as sugar, for example lactose, sucrose, manat or sorbet, cellulose preparations, and/or calcium phosphates such as tricalcium phosphate or calcium hydrogen phosphate, further mixing agents such as starch using, for example, malt, wheat, rice or potato starch, gelatin , tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and/or, if desired, explosives such as the above-mentioned starches, further carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, algalic acid or a salt thereof such as sodium alginate. Auxiliaries are primarily rice yield regulating agents and lubricants such as silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol. Dragon cores are equipped with suitable, possibly stomach-juice-resistant coatings whereby, among other things, concentrated sugar solutions are used which may contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions in suitable organic solvents or, for the production of gastric-juice-resistant coatings, solutions of suitable cellulose preparations such as ethyl cellulose phthalate or hydroxypropyl methyl cellulose phthalate. Capsules are capsules made of gelatin as well as soft, closed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. The stick capsules can contain the active ingredient 1 in the form of a granule, for example with fillers such as lactose, mixing agents such as starch, and/or thickeners such as talc or magnesium stearate, and possibly with stabilizers. In soft capsules, the active ingredient is preferably dissolved or suspended in suitable oily excipients such as fatty oils, paraffin oil or liquid polyethylene glycols, to which possibly stabilizers and/or antibacterial agents may be added. The tablets or dragee coatings and capsule casings may contain dyes or pigments, for example for identification or characterization of different doses of active ingredient.

Starting materials;

New starting substances and/or intermediate products as well as methods for their production must be described in more detail. Such starting materials are preferably used and reaction conditions are chosen so that the compounds indicated as preferred are obtained.

In the preparation of all starting materials, free functional groups which are not to participate in the reaction in question can be present unprotected or in a protected form, for example protected by the protective groups mentioned above under method a). These protecting groups can then be set free at suitable times during the reactions described under method f).

The starting materials 1 procedure a) are known or, to the extent that they are new, can be prepared by methods known per se, for example from hydrazine or suitable derivatives thereof, the compounds of formula III, further from suitable amino acids or their analogues, for example with one or two of the aforementioned side chains R3 and R4, the compounds of formula IV.

The compounds of formula III are, for example, accessible from compounds of the formula:

where Rn is hydrogen or an amino protecting group, as described above under method b), in particular tert-lower alkyl oxycarbonyl such as tert-butoxycarbonyl, aryl lower alkyl oxycarbonyl such as benzyloxycarbonyl or 9-fluorenylmethoxycarbonyl, or one of the above-mentioned acyl amino protective groups, while for the preparation of a compound of formula I alkylates while introducing R7 with a compound of formula XII as described above under method e), or introduces the residue R7 by reaction

between suitable carbonyl compounds with the free amino group 1 compound of formula VIII or their acylated derivatives and then the following reduction of the obtained hydrazone to hydrazine adducts with the formula:

whereby the residues in all the aforementioned compounds have the above-mentioned meaning and functional groups in the participating reagents that do not participate in the reaction, are optionally protected, optionally split by the protective group Rn, as long as it does not correspond to one of the residues Rq 1 compounds of formula I, and /or further protecting groups, and reacts the residues Rq except for hydrogen by condensation under the conditions mentioned above under method b) with acids of formula VI.

The carbonyl compounds used for the preparation of the compounds of formula XVI and suitable for the introduction of R7 are aldehydes or ketones whose reactive carbonyl group after reaction with the compounds of formula XV and the subsequent reduction is part of one of the residues Ry, preferably aldehydes, which are suitable for the introduction of lower alkyl, cyclohexyl lower alkyl or phenyl-lower alkyl.

The reaction of the carbonyl compounds with the compounds of formula XVI to the corresponding hydrazones takes place under the usual conditions for the reaction of carbonyl compounds with amines, preferably the polar organic solvents, for example ethers such as tetrahydrofuran or diethyl ether, alcohols such as methanol or ethanol, carboxylic acid amides such as dimethylformamide or esters such as acetic acid ethyl ester, or in aqueous solution, - preferably in methanol, further in the presence or absence of acidic catalysts, for example carboxylic acids such as formic or acetic acid, or sulphonic acids or p-toluenesulphonic acid, at temperatures between 0<*>C and the reflux temperature of the reaction mixture , preferably at temperatures of 20°C to the reflux temperature of the reaction mixture.

The reduction of the obtained hydrazones takes place preferably by hydrogenation in the presence of a suitable catalyst. Suitable catalysts for hydrogenation are metals such as nickel, iron, cobalt or ruthenium, or noble metals or their oxides, such as palladium or rhodium, or their oxides, possibly for example on suitable supports such as barlum sulphate, aluminum oxide or activated carbon, or as skeletal catalysts such as Raney nickel. Useful solvents for catalytic hydrogenation are, for example, water, alcohols such as methanol or ethanol, esters such as acetic acid ethyl ester, ethers such as dioxane, chlorohydrocarbons such as dichloromethane, carboxylic acids such as dimethylformamide, or carboxylic acids such as lyseddlk, or mixtures of these solvents. The hydrogenation takes place at temperatures from 10 to 250<*>C, preferably from room temperature to 100*C and at hydrogen pressure from 1 to 200 bar, preferably 1 to 10 bar, in the usual apparatus.

Particularly preferred for the preparation of the compounds of formula XV are reaction conditions analogous to those described in "J. Chem. Soc. Perkin I", 1712 (1975).

The compounds of formula IV are available, for example, by reduction of amino acids of the formula

where Rjo is hydrogen or one of the umier method a) mentioned amino protecting groups, in particular tert-lower alkyl oxycarbonyl such as tert-butoxycarbonyl, aryl lower alkyl oxycarbonyl such as benzyloxycarbonyl or 9-fluorenylmethoxycarbonyl, or one of the acyl amino protective groups mentioned therein and R3

and R4 has the meaning mentioned for the compounds of formula I, preferably from amino acids of the formula::

where the residues have the indicated meaning, to aldehydes of the formula: where the residues have the mentioned meaning, preferably to aldehydes of the formula: where the residues have the indicated meaning (obtainable for example from compounds of formula XVIIIA), by reacting these aldehydes with a ylide compound, preferably a sulfur ylide compound, to an epoxide of the formula: where the residues have the indicated meaning, preferably to compounds of the formula:

(obtainable for example from compounds of formula XIXA), where the residues have the indicated meaning, optional removal of the protecting group Kjj as long as it does not correspond to one of the residues Rg 1 compounds of formula I, and acylation of the amlno group 1 the resulting compound with acids of formula VIII, whereby the residues have the indicated meaning, under the conditions described for method b).

The reduction of the amino acids with the formulas XVIII or XVIIIA to the corresponding aldehydes XIX and XIXA follows, for example, by reduction to the corresponding alcohols with subsequent oxidations to the aforementioned aldehydes.

The reduction to the alcohol takes place, for example, by hydrogenation of the acid halides or also other activated carboxylic acid derivatives mentioned in method b) under the conditions mentioned for the hydrogenation of hydrazones obtained from compounds of formula XVI or with complex hydrides such as natrlumborhydrld. The subsequent oxidation of the alcohols obtained is possible, for example, under conditions for the oxidation of the compounds of formula I where R5 is hydroxy and Rg is hydrogen to those where R5 and Rg jointly mean oxo, as described under the further process precautions, or possible by oxidation of the hydroxy group with a sulfoxide such as dimethyl sulfoxide in the presence of a reagent that activates the hydroxy group, for example a carboxylic acid chloride such as oxalyl chloride, an inert solvent such as a halogenated hydrocarbon such as dichloromethane, and/or an acyclic or cyclic ether such as tetrahydrofuran at -80* C to 0"C, for example at -78*C to -50'C.

Also the direct reduction of the amino acids to the aldehydes is possible, for example by hydrogenation in the presence of a partially poisoned palladium catalyst or by reduction of the corresponding amino acid ester, for example the lower alkyl ester such as the ethyl ester, with complex hydrides such as borohydrides, for example sodium borohydride, or preferably aluminium- hydrides, for example lithium aluminum hydride, lithium tri-(tert-butoxy) aluminum hydride or especially diisobutyl aluminum hydride, 1 apolar solvents, for example in hydrocarbons or aromatic solvents such as toluene, at -100*C to 0<*>C, and preferably -70*C to 30°C, with subsequent reaction to the corresponding semicarbazones, for example with the corresponding acid salts of semicarbazones such as semicarbazal hydrochloride, 1 aqueous solvent systems such as alcohol/water, for example ethanol/water, at temperatures between -20 *C and +60<*>C, preferably 10<*>C to 30<*>C, and reaction of the semlcarbazone obtained with e t reactive aldehyde, for example formaldehyde, in an inert solvent, for example a polar, organic solvent such as a carboxylic acid amide, for example dimethylformamide, at temperatures between -30*C and +60"C, preferably 0<*> C to 30<*>C, and then an acid, for example a strong mineral acid, for example hydrohalic acid 1 aqueous solution, optionally in the presence of the solvents used above, at temperatures between -40<*>C and +50<*> C, preferably between -10*C and +30<*>C. The corresponding esters are obtained by reaction of the amino acids with corresponding carboxylic acids, for example ethanol, analogous to the conditions used in the condensation under method b), for example by reaction with inorganic acid halides such as tlonyl chloride, 1 organic solvents such as mixtures of aromatic and alcoholic solvents , for example toluene and ethanol, at temperatures between -50<*>C and +50<*>C, preferably between

-10*C and +20<*>C.

The preparation of the compounds of formula XIX and XIXA takes place in a particularly preferred manner under conditions analogous to those mentioned in "J. Org. Chem.", 47, 3016 (1982) or "J. Org. Chem.", 43, 3624 (1978).

A suitable sulfur ylide for reacting the compounds of formula XIX or XIXA to the epoxides of formula XX or XXA is, for example, a dialkylsulfonium methylide such as dimethylsulfonium methylide, an alkyl- or phenyl-dlalkylamlnosulfoxonium methylide such as methyl- or phenyl-dimethylamlnosulfoxonium methylide or a dlalkylsulfoxone lummethyl ld such as dlmethyl or dlethylsulfoxone lummethyl ld.

The sulfur-ylide compound in question is preferably prepared in situ from the corresponding sulfonium or sulfoxonium salt and a base, for example sodium hydride, in a dipolar, aprotic solvent, for example dlmethylsulfoxide, or an ether such as tetrahydrofuran or 1,2-di- methoxyethane, and then reacted with the compounds of formula XIX or XIXA. The reaction usually takes place at room temperature, during cooling, for example to -20"C or during slight heating, for example to 40<*>C. The simultaneously formed sulphide, sulphide acid and sulphoxide are removed in the subsequent aqueous work-up.

The reaction with a sulfur ylide takes place in a particularly preferred manner analogous to the conditions described in "J. Org. Chem.", 50, 4615 (1985).

The compounds of formula XX (preferably XXA) can be prepared from compounds of formula XIX (preferably XIXA), as defined above by their reaction with a trilower alkylsilylmethyl Grignard compound, for example prepared from the corresponding halomethylsilane such as chloromethyl silane, in an inert solvent , for example an ether such as dloxane or diethyl ether, at temperatures between 0<*>C and 50<*>C, for example between room temperature and approx. 40<*>C with subsequent elimination during removal of the silyl residue and formation of a double bond, for example by means of a Lewls acid such as BF3, whereby an amino protecting group R^o * is preferably also cleaved by an inert solvent part, for example an ether as diethyl ether, or a halohydrocarbon such as dichloromethane or a mixture thereof, at temperatures between

-50*C and the reflux temperature, especially between 0<*>C and 30<*>C, if necessary new acylation during the introduction of an amino-

protecting group as R^q as defined above, and oxidation of the obtained double bond to oxirane, preferably with a percarboxylic acid such as m-chloroperbenzoic acid in an inert solvent, for example a halogenated hydrocarbon such as dichloromethane, at temperatures between -20*C and the reflux temperature of the mixture, for for example at 10°C to 30*C.

The starting materials for the methods b), c) and d) are known or can, 1 to the extent that they are new, be prepared 1 according to 1 and per se known methods, for example the compounds of formula V can be obtained from suitable hydrazine derivatives of formula III where the rest Rg means hydrogen and the other residues have the meaning mentioned for the compounds of formula V, and suitable epoxides of formula IV where the residues have the meaning given to compounds of formula V (method b), the compounds of formula VII from suitable hydrazln derivatives with formula III where the residues have the meaning given for compounds of formula VII and suitable epoxides of formula IV where Ri means hydrogen and the other residues have the meaning given for compounds of formula VII (method

c), and the compound of formula IX from suitable hydrazln derivatives of formula III where Rg means hydrogen and the other

residues have the meaning given for compounds of formula IX (method d) and suitable epoxides of formula VI where Ri means hydrogen and the other residues have the meaning given for compounds of formula IX (method d), analogous method a) , possibly during the application and cleavage of protective groups.

The compounds of formula I' where the substituent has the above meaning can for example be prepared from compounds of formula III<*>:

where the residues have the meaning given for compounds of formula I, as described in method b), by reaction with a compound of formula IV, whereby functional groups present that should not participate in the reaction that are present there are protected and can be set free after the reaction .

Preferred for method d) are the starting compounds of formula:

where R 3 and R 7 have the meaning given for the compounds of formula I, as well as the salts of the aforementioned compounds, as long as salt-forming groups are present, which are intermediate compounds..

These may in particular be protected on one or both amino groups whereby, when there are two amino groups, these may be the same or different.

As amino protecting groups, for example, the groups mentioned above under method a) are used. The residues R3 and R7 mentioned for compounds of formula II have the meaning given above for the compounds of formula I in the definition of R3 and R7.

Very preferred are the compounds of formula II where R 3 is cyclohexyl lower alkyl, phenyl lower alkyl or p-fluorophenyl lower alkyl and R 7 means lower alkyl, cyclohexyl lower alkyl, phenyl lower alkyl, p-cyanophenyl lower alkyl or p-fluorophenyl lower alkyl, as well as the salts of the aforementioned compounds if there are salt-forming groups.

Particularly preferred are the compounds of formula II, where R 3 means phenyl lower alkyl and R 7 means lower alkyl, cyclohexyl lower alkyl or phenyl lower alkyl, as well as the salts of the aforementioned compounds if salt-forming groups are present.

First and foremost preferred are the compounds of formula II where R3 means cyclohexylmethyl, benzyl or p-fluorobenzyl and R7 means n-butyl, isobutyl, cyclohexylmethyl, benzyl, p-fluorobenzyl or p-cyanobenzyl, as well as the salts of the aforementioned compounds if present salt-forming groups.

Particularly preferred are the compounds of formula II, where R3 means benzyl and R7 means isobutyl, cyclohexylmethyl or benzyl, as well as the salts of the aforementioned compounds, if salt-forming groups are present.

The most preferred compounds are the compounds of formula II mentioned in the examples.

The compounds of formula II in which the substituents have the meanings indicated above and their salts, if salt-forming groups are present, are prepared, for example, by adding a hydrazine derivative of the formula: where Rio means an amino protecting group to epoxide with the formula:

Where Rn means an amlnoprotecting group, and

possibly one according to the method indicated above

a) obtained compound of formula II is transferred with at least one salt-forming group to its salt or an obtained salt 1 den

free compound or to another salt, and/or optionally obtained isomeric mixtures are separated and/or protective groups present in a compound of formula II are cleaved off and/or

a compound according to the invention with formula II is converted into another compound according to the invention with formula II.

The production and conversion of salts, separation of isomer mixtures, cleavage of protective groups and conversion of compounds of formula II takes place analogously to what is stated above for compounds of formula I.

Particularly preferred is the preparation of starting products of formula II where the substituents have the indicated meaning, by protection group removal from compounds of formula II where one or both amino groups are protected with amino protecting groups, in particular under conditions for hydrolysis of compounds of formula I as described under the further precautions.

The methods for the addition of compounds of formula XVI to those of formula XXA are described above under method a) in the preparation of compounds of formula I.

The production of the protected compounds of formula I takes place, for example, according to any of the methods mentioned so far, especially from compounds of formula II and IV, whereby functional groups 1 these compounds are optionally protected with protective groups as described under method a ).

The acids of the formulas VI, VIII, XVII and XXI as well as the compounds with nucleofuge groups of the formula XII, XIII are known or, to the extent that they are new, can be prepared by methods known per se.

The following examples are intended to illustrate the invention without limiting it.

The temperatures are given in °C. If temperature specifications are not available, the reaction takes place at room temperature. The Rf values which indicate the relationship between the running distances of the substances in question and the running distance of the eluent front are determined on silica gel thin-layer plates by thin-layer chromatography (DC) in the following eluent component systems.

DC eluent systems:

The abbreviations "Rf(A)" mean, for example, that the Rf value was determined in the solvent component system A. The quantity ratio between the solvents Between them is always indicated as 1 volume fraction.

HPLC graduations:

In 20* -» 100* acetonitrile:0.05* trifluoroacetic acid in

water:0.05* trifluoroacetic acid during 35 minutes.

II 0* -» 40* acetonitrile:0.05* trifluoroacetic acid 1

water:0.05* trifluoroacetic acid during 30 minutes.

III 20* -» 60* acetonitrile:0.05* trifluoroacetic acid i

water:0.05* trifluoroacetic acid during 60 minutes.

IV 10* 50* acetonitrile:0.05* trifluoroacetic acid in water:0.05* trifluoroacetic acid over 60 minutes.

Column (250 mm x 4.6 mm) filled with "Reversed-Phase"-material Cig-Nucleosil"® (5 pm average grain size, with octadecyl-silanes covalently derivatized silica gel, Macherey & Nagel, Duren, Germany). Detection by UV -absorption at 215 nm Retention times (tRet) are given in minutes Flow rate 1 ml/min.

Flash chromatography and medium pressure chromatography use the same abbreviations to indicate the eluent system.

The additional abbreviations and abbreviations used have the following meaning:

Mass spectroscopic measurement values are obtained either by conventional MS or 1 according to "Fast-Atom-Bombardment"

(FAB—MS) method. The mass specifications apply in the first case to the non-protonated molecular ion (M)<+> or the protonated molecular ion (M+H)<+.>

The values for the proton-nuclear resonance spectroscopy (^-H-NMR) are given in ppm (parts per million), calculated on tetramethylsilane as internal standard, s - singlet, d - doublet, t - triplet, q - quartet, m - multiplet, dd - double doublet, br - wide.

The values for the IR spectra are given in cm"<1>, in round brackets there is the relevant resolution part. If indicated, s means a strong, m a medium and w a weak intensity for the signal in question.

The residue with the designation -[Phe^Phe] means the divalent residue of 3(S)-amino-4-phenyl-1-(N-benzylhydrazino)-butan-2(S)-ol and has the formula:

The residue with the designation -[Phe^Cha] means the divalent residue of 3(S)-amino-4-phenyl-1-(N-cyclohexylmethylhydrazlno)-butan-2(S)-ol and has the formula:

The residue with the designation -[Phe^Leu] means the divalent residue of 3(S)-amino-4-phenyl-1-(N-isobutylhydrazino)-butan-2(S)-ol and has the formula:

The residue with the designation -[Phe^Nle] means the residue of 3(S)-amino-4-phenyl-1-(N-n-butylhydrazino)-butan-2(S)-ol and has the formula:

The residue with the designation -[Phe^Cp-FjPhe] means the divalent residue of 3(S)-amino-4-phenyl-1-(N-(p-fluorophenylmethyl)-hydra-zlno)-butane-2(S)- ol and has the formula:

The residue with the designation -[(p-F)Phe<NN>(p-F)Phe] means the divalent residue of 3(S)-amino-4-(p-fluorophenyl)-1-(N-(p-fluoro-phenylmethyl)- hydrazino)-butan-2(S)-ol and has the formula:

The residue with the designation -[Ph<e>N<N>(p-CN)Phe] means the divalent residue of 3(S)-amino-4-phenyl-1-(N-(p-cyanophenylmethyl)-hydrazino )-butan-2(S)-ol and has the formula:

The residue with the designation -[Cha^Leu] means the divalent residue of 3(S)-amino-4-cyclohexyl-1-(N-Isobutyl-hydrazino)-butan-2(S)-ol and has the formula:

For designation of divalent residues of natural α-amino acids, the usual abbreviations in peptid chemistry are used. In this way, however, the amino acids that appear to the right of -[PheNNphe] , -[PheNNcha] , -[Phe^<L>eu] , -[Phe^Nle] , -[Phe^p-FjPhe] , -[( p-FjPhe^p-FjPhe] , -[Phe^p-CNjPhe] or -[Cha^<L>eu] , in contrast to the usual peptide nomenclature, where the amlnoterminus is on the left and the carboxy terminus on the right, the binding carboxy group to the left, which is indicated by an arrow (*-), symbolizing the reversal of the bond direction. The configuration on the o-carbon atom is indicated, if known, by the prefix (L) or

(D). Tyrosine residues which are etherified on the phenolic hydroxy group with the residue R are indicated by Tyr(OR). Nie means the rest of

norleucine.

Example 1; Boe- [Phe^Phe] -Boe

A solution of 300 mg (1.14 mmol) of (2R)-[1'(S)-Boc-amino-2'-phenylethyl]oxirane ("J. Org. Chem.", 50, 4615 (1985)) and 253 mg (1.14 mmol) of tert-butyl-3-benzyl-carbazate (WJ. Org. Chem. Soc", Perkin I, 1712 (1975)) in 4 ml of methanol is heated for 12 hours under reflux. After cooling the reaction mixture at 0'C, a large part of the title compound precipitates out. The mother liquor is evaporated and the residue is dissolved in a little methylene chloride. After adding hexane dropwise, a further part of the title compound precipitates out as a white precipitate.

FAB-MS (M+H)<+> - 486; tRet(<I>) - 25.8 min.;

Rf(E) - 0.70.

Example 2; Z-fLJ-Val-lPhe^PheiM(L)-Val-Z):

191 mg (0.76 mmol) Z-(L)-valln, 336 mg (0.76 mmol) BOP and 103 mg (0.76 mmol) HOBt are dissolved in 5 ml of a 0.3 M solution of NMM in DMF, adds after 10 min. 100 mg (0.25 mmol) H-CPhe<NNp>heJ-H-SBXl and stir for 2 hours at RT under nitrogen atmosphere. The reaction mixture is evaporated, the residue is dissolved in 1 methylene chloride and washed twice with saturated sodium bicarbonate solution. The organic phases are filtered through water, evaporated and the residue is purified by means of a chromatograph on Clselgel with methylene chloride:ether (1:1). After lyophilization of the product-containing fractions from dioxane, the title compound is obtained as a white solid.

FAB-MS (M+H)<+> - 752; tRet(<J>) " 27»8 «in.;

Rf(E) - 0.45.

The starting material is produced as follows:

a) H-[ Phe^ Phe]- H• 3HC1:

A solution of 280 mg (0.58 mmol) Boc-CPhe^Phe]-Boe from

example 1 1 10 ml 4N hydrogen chloride 1 dioxane is stirred for 1 2 hours at RT under a nitrogen atmosphere and then lyophilized. Renewed lyophilization from dioxane:tert-butanol gives the title compound as a fluffy solid.

FAB-MS (M+H)<+> - 286; <t>Ret(II) - 23.1 min.;

Rf(C) - 0.17.

Example 3: Boc-(L )-Val-[Phe^-PheM (L)-Val-Boe):

Analogously to example 2, one obtains from 50 mg (0.13 mmol) H_[Pne<NNp>he]_H.3HC1f 83 mg (0.83 mmol) Boc-(L)-valln, 168 mg (0.38 mmol) BOP , 51 mg (0.38 mmol) HOBt and 2.5 ml 0.3 M NMM 1 DMF after chromatographic purification on silica gel with chloroform:methanol (95:5) lysates from the dioxane title compound.

FAB-MS (M+H)<+> - 684; tRet(I) - 27.4 min.;

Rf(E) - 0.38.

Example 4: Boe- [Phe^Cha] -Boe:

Analogously to example 1, one obtains from 231 mg (0.8 mmol) (2R.3S)-1-[3-Boc-amino-2-phenylethyl]oxirane and 200 mg (0.88 mmol) tert-butyl-3-cyclohexylmethyl -carbazate the title compound as a white precipitate from hexane.

FAB-MS (M+H)<+> - 492; tRet(I) " 30»4 min.;

Rf(E) - 0.78.

The starting material is produced as follows:

a) tert-butyl-3-cyclohexylmethyl-carbazate:

10.2 g (45.1 mmol) of cyclohexylcarbaldehyde-tert-butoxycarbonylhydrazone, dissolved in 400 ml of methanol, is hydrated in the presence of 5.1 g of 5* platinum-on-carbon at RT and 4 atm. hydrogen pressure. After the reaction is finished, the catalyst is filtered off and the filtrate is evaporated. The residue is dissolved in methylene chloride and washed with water. After evaporation of the organic phase, the title compound is obtained as a colorless resin.

^H-NMR (200 MHz, CDCl 3 ): 6.1 (s, br, 1H), 3.9 (s, br,

1H), 2.65 (d, 2H), 1.8-0.75 (m, 11H), 1.45 (s, 9H);

<tg>et(I) - 32.0 min.; Rf(E) - 0.75.

b) C. cyclohexylcarbaldehyde-tert-butoxsvcarbonylvlhvdrazone;

A solution of 10.8 g (81.2 mmol) of tert-butylcarbazate and

10.1 g (90 mmol) of cyclohexylcarbaldehyde and 1,400 ml of ethanol are heated for 2 hours under reflux. Half of the solvent is then distilled off and the title compound is precipitated by the addition of water. This is used directly further in a).

Example 5: H-(L )-Val-[PheM-PheX (L )-Val )-H- 3HC1:

A solution of 40 mg (0.06 mmol) Boc-(L)-Val-[Phe^Phe]«—

((L)-Val)-Boc from example 3 in 4 ml of 4N hydrogen chloride in dioxane is stirred for 1 hour at RT. It is then diluted with dioxane and, after lyophilization, the title compound is obtained as hydrochloride.

FAB-MS (M+H)<+> - 484; tRet(II) - 25.8 min.;

Rf(A) - 0.45.

Example 6; N-1 iomor f ol inocarbonyl - (L )-Val-[PheliNPhe]«-(N-thiomorpholinocarbonyl-(L)-Val): To a solution of 20 mg (0.03 mmol) H-(L)-Val -[Phe<NN>Phe]«—

((L)-Val)-H*3HCl from example 5 in 0.5 ml of DMF, 35 µl (0.25 mmol) of triethylamine and 16 mg (0.1 mmol) of (4-thiomorpholinylcarbonyl) chloride are added one after the other at RT and the whole is stirred for 1 hour at RT. The reaction mixture is diluted with

chloroform and washed with saturated sodium chloride solution. The organic phase is filtered through water, evaporated and the residue is chromatographed on silica gel with a gradient of chloroform: methanol (15:1 -» 8:1). Product f raks J The ion is evaporated and combined with methylene chloride: DIPE. The title compound is obtained as a fine solid after lyophilization from dioxane.

FAB-MS (M+H)<+> - 742; <*>Ret(I) - 21.6 min.;

Rf(D) - 0.54.

The starting material is produced as follows:

a) (4-thiomorpholinylcarbonyl) chloride:

To a solution of 85 ml (165 mmol) 20 *-ig phosgene i

toluene is added dropwise at 0°C to a solution of 10 g (97 mmol) tlomorpholine in 200 ml toluene and the white suspension is stirred for 1 hour at RT. Excess phosgene is driven off by introducing nitrogen, the suspension is filtered and the filtrate is evaporated. The title compound is obtained as a yellow oil.

IR (CH 2 Cl 2 , cm"<1>): 1735, 1450, 1440, 1405, 1370, 1290,

1180.

TCic«em pel 7: N-morpholinocarbonyl-(L)-Val- [Phe^Phe] *-(N-■orpholinocarbonyl-(L)-Val): To a solution of 100 mg (0.25 mmol) H -CPhe^Phel-H-SHCl from example 2a), 163 mg (0.76 mmol) N-morpholinocarbonyl-(L)-valln and 288 mg (0.76 mmol) HBTU 1 2 ml DMF are placed 210

pl (1.52 mmol) triethylamine and the whole is stirred at Rt for 16 hours under nitrogen. The reaction mixture is completely evaporated, the residue is dissolved in 1 methylene chloride and washed with saturated sodium chloride solution. The organic phase is filtered through water, evaporated and chromatographed with methylene chloride:methanol (15:1). The title connection is removed

methylene chloride:hexane and after lyophilization from dioxane:tert-butanol the title compound is obtained as a fine solid.

FAB-MS (M+H)<+> - 710; tRet(I) - 16.3 min.;

Rf(E) - 0.16.

The starting material is produced as follows:

a) N-morpholinocarbonyl-(L)-vallin:

2.7 g (8.4 mmol) N-morpholinocarbonyl-(L)-valine benzyl ester

dissolve 1 75 ml of eddlkester and hydrate 1 in the presence of 500 mg of 10* palladium-on-carbon at 1 atm. hydrogen pressure and RT for 3 hours. The catalyst is filtered off and the following is obtained

Evaporation of the solvent gave the title compound as a colorless oil.

<*>H-NMR (300 MHz, CD30D): 4.15 (m, 1H), 3.65 (m, 4H), 3.40 (m, 4H), 2.12 (m, 1H), 0 .95 (2d, 6H).

b) N-morpholinocarbonyl-(L)-valine benzester:

To a solution of 4 g (10.5 mmol) of (L)-valine-benzyl ester-4-toluenesulfonate in 56 ml of methylene chloride is added 0.8 ml (8.1 mmol) of (morpholinocarbonyl) chloride (Production: "J. Med. Chem.»', 31, 2277 (1988)) and 4.1 ml (24.1 mmol) of N-ethyldiisopropylamine and the whole is stirred for 24 hours at RT. The reaction mixture is diluted with diethyl ether and successively with 1N hydrochloric acid, water, saturated sodium bicarbonate solution and salt solution (sole). The organic phase is dried over sodium sulfate and evaporated. After chromatography on silica gel with noble ester, the N-morpholinocarbonyl-(L)-valine benzyl ester is obtained as a colorless oil. The ester is used immediately further in step a ).Example 8: Phenylacetyl - (L )-Val-[Phe^Phe]*^ N-phenylacetyl- fD-Val): Analogous to example 7, the title compound is obtained from 100 mg (0.25 mmol) H-[Phe^Phe]-H*3HC1 from example 2a), 143 mg (0.61 mmol) phenylacetyl-(L)- valine (Preparation: "Mem. Tokyo Univ. Agrlc", 20, 51 (1978)), 230 mg (0.61 mmol) HBTU and 200 µl (1.42 mmol) triethylamine after chromatographic purification with methylene chloride:ethermethanol (20: 20:1) and lyophilization from dioxane:tert-butanol.

FAB-MS (M+H)<+> - 720; tRet(<I>) " 23»7 min.;

Rf(G) - 0.21.

Example 9: N-(3-pyridylacetyl MLj-Val-CPhe^-PheiMlM 3-pyr idyl acetyl)-(L )-Val): Analogous to example 7, one obtains from 100 mg (0.25 mmol) H-CPhe<NNp >hel-H-SBXl from Example 2a), 576 mg (1.52 mmol) HBTU, 358 mg (1.52 mmol) N-(3-pyridylacetyl)-(L)-valine and 316 µl (2.3 mmol ) triethylamine after chromatographic purification with chloroform:methanol (5:1) and lyophilization from dioxane:tert-butanol, the title compound as a white solid.

FAB-MS (M+H)<+> - 722; tRet*11) - 27»9 min.;

Rf(A) - 0.71.

The starting material is produced as follows:

a) N- O- pyrldvlacetvl )-( L)- valine:

3.4 g of N-(3-pyridylacetyl)-(L)-valine tert-butyl ester

dissolve in 20 ml trifluoroacetic acid:methylene chloride (1:1) and stir at RT 1 for 16 hours. The reaction solution is evaporated

completely In and the rest is diluted with DIPE. The title compound is obtained as a white, amorphous solid.

<1>H-NMR (200 MHz, CD3OD): 8.9-8.6 (m, broad, 1E),

8.5 (m, 1H), 7.95 (m, 1H), 4.33 (m, 1H),

3.93 (s, 2H), 2.2 (m, 1H), 0.98 (2d, 6B). b) N-(3-pyridylacetyl)-(L)-valin- tert-butyl ester;

To a solution of 3.36 g (16 mmol) (L)-valine tert-butyl ester EC1, 2 g (14.5 mmol) 3-pyridylacetic acid and 2.17 ml (14.3 mmol) cyanophosphoric acid diethyl ester in 20 ml of DMF are added dropwise at 0°C to 4.2 ml of triethylamine. The reaction mixture is stirred for 148 hours at RT, then diluted with methylene chloride and washed with 10 µg of sulfuric acid and with saturated sodium bicarbonate solution. The organic phase is filtered through water and gives, after evaporation of the solvent, N-(3-pyridylacetyl)-(L)-valine-tert-butyl ester, which is immediately used further under a).

Example 10; Boc-(L)-Val-[PheNNCha]«-((L)-Val )-Boc

Analogous to example 7, starting from 500 mg (1.25 mmol) E-CPhe<NN>chal-E-SBCl, 1.08 g (4.98 mmol) Boc-(L)-valine, 1, 89 g (4.98 mmol) of EBTU and 1.39 ml (9.96 mmol) of triethylamine after chromatographic purification on silica gel with methylene chloride ether (1:1) and lyophilization from dioxane, the title compound as a fluffy solid.

FAB-MS (M+E) + - 690; tRet*1) " 29>3 min.;

Rf(E) - 0.48.

The starting materials are produced as follows:

a) H-[ Phe^ Cha]- H• 3HC1:

1.10 g (2.2 mmol) Boc-CPhe^ChaJ-Boc from Example 4

dissolved in 1 20 ml 4N hydrogen chloride 1 dioxane and stirred for 1 3 hours at RT. After lyophilization of the reaction solution, the title compound is obtained as hydrochloride.

FAB-MS (M+H)<+> - 292; tRet(II) - 27.3 min.

Example 11: Z-CLJ-Val-CPhe^ChaM (L)-Val-Z:

Analogous to example 2, the title compound is obtained from 50 mg (0.12 mmol) H-CPhe^Chal-H-SHCl from example 10a), 94 mg (0.37 mmol) Z-(L)-valln, 165 mg (0, 37 mmol) BOP, 51 mg (0.37 mmol) EOBt and 2.5 ml 0.3 M NMM 1 DMF after chromatographic purification on silica gel with methylene chloride ether (1:1) and lyophilising from dioxane.

FAB-MS (M+H)<+> - 758; tRet(I) - 29.1 min.;

Rf(H) - 0.55.

Example 12: Boe- [Phe^Leu] -Boe:

Analogous to example 1, the title compound is obtained as a precipitate from hexane by starting from 1.0 g (3.8 mmol) (2R)-[1'(S)-Boc-amino-2'-phenylethyl]oxirane and 715 mg ( 3.8 mmol) tert-butyl-3-isobutyl-carbazate (Preparation: "J. Chem. Soc.", Perkin I, 1712 (1975)).

FAB-MS (M+H)<+> - 452; tRet(I) - 27.2 min.;

Rf(I) - 0.55.

Example 13; Z-(L)-Val-[PlierøiJeU]*.((L)-Val-Z:

Analogous to example 2, the title compound is obtained by starting from 60 mg (0.172 mmol) H—[Phe^Leu]-H*3HC1. 125 mg (0.50 mmol) Z-(L)-vallin, 221 mg (0.50 mmol) BOP, 67 mg (0.50 mmol) HOBt and 3.3 ml 0.3 M NMM 1 DMF after chromatographic purification on silica gel with methylene chloride ether (1:1) and lyophilization from dioxane.

FAB-MS (M+H)<+> - 718; tRet(<I>) - 26.8 min.;

Rf(H) - 0.38.

The starting material is obtained as follows:

a) H-[ Phe^ Leu]- H* 3HC1:

Analogous to example 10a), the title compound is obtained from

1.21 g (2.48 mmol) Boc-CPhe^Leu]-Boe from Example 12 as lyophilisate.

FAB-MS (M+H)<+> - 252; tRet^<1>1) 20•»9 min.;

Rf(K) - 0.23.

Example 14; H-(L )-Val-[Phe^ChaM (L )-Val-H* 3HC1:

Analogous to example 10a), the title compound is obtained as hydrochloride from 632 mg (0.91 mmol) Boc-(LJ-Val-CPheNNcha]—

((L)-Val)-Boc from Example 10 after lyophilization.

FAB-MS (M+H)<+> - 490; tRet*<1>1) " 29 »4 min.;

Rf(K) - 0.23.

Example 15: H-(3-pyridylacetyl)-(L)-Val-[Phe^Leu]«-(N-(3-pyridylacetyl)-(L)-¥al): Analogous to example 9, the title compound is obtained from 90 mg (0.25 mmol) H— [Phe^Leu]-H*3HCl from Example 13a), 358 mg (1.52 mmol) N-(3-pyridylacetyl)-(L)-valine, 576 mg (1.52 mmol) HBTU and 316 µl (2.5 mmol) triethylamine after chromatographic purification with methylene chloride:methanol (15:1) and lyophilization from dioxane:tert-butanol:water.

FAB-MS (M+H)<+> - 688; tRet(IV) " 15»5 min.;

Rf(D) - 0.37.

T<g>k<g>ftinpfti 1 h: N-trifluoroacetyl-[PheM'(p-F )Phe] -Boe:

A solution of 4.0 g (15.4 mmol) of 2(R)-[1'(S)-(trifluoroacetyl-amino)-2'-phenylethyl]-oxirane and 3.89 g (16.2 mmol) of tert -butyl-3-(p-fluorophenyl-methyl)-carbazate in 35 ml of methanol is heated for 1 approx. 20 hours 1 bomb pipe for approx. 80°C. The reaction mixture is evaporated, the residue is dissolved in a little dichloromethane and the title compound is precipitated with hexane (refrigerator). Additional product is obtained by column chromatography (S102, methylene chloride:ether 95:7).

DC Rf(J) - 0.57; tRet^<1>) - 24»3 min.;

FAB-MS (M+H)<+> - 500.

The starting materials are produced as follows:

a) N-3(S)-(Boc-amino)-2(R.Sl-hydroxyl-4-phenyl-l-trimethyl-sllvl-butane: Under ^-atmosphere one starts from 24.7 g (1, 02 mol) of magnesium in 100 ml of absolute ether and a little iodine is added over 35 minutes and at the same time 132.5 ml (0.95 mol) of chloromethyltrimethylsilane and 300 ml of ether, whereby the temperature is kept at 38<*>C with the aid of an ice bath. The resulting reaction mixture is then stirred for 11V4 hours at RT. After cooling to -60°C, a suspension of 48.6 g (0.195 mol) of N-Boc-phenylalanalnal (Preparation: D.J. Kempf, "J . Org. Chem.", 51» 3921 (1986)) in 1.1 1 ether during 40 min. During 90 min. the reaction mixture is heated

to RT and stirred for a further 90 min. by this

temperature. Then pour in 2 1 ice water and 1.5 1 10 lb aqueous sulfuric acid. The separated aqueous phase is extracted 2 x 500 ml of ether. All ether extracts are washed with 500 ml of 10 µg sulfuric acid and twice with saline solution. After drying over sodium sulfate, it is evaporated under vacuum and the obtained title compound is used further without further purification.

DC Bf(L) - 0.6; FAB-MS (M+H)<+> - 338.

b) l-phenvl-3-butene-2(S)-amln:

To a solution of 18.8 g (0.055 mol) 3(S)-(Boc-amino)-2(B,S)-hydroxy-4-phenyl-1-trimethylsilyl-butane in 420 ml of methylene chloride is added at 5' C during 10 minutes 35.6 ml (0.28 mol) of an approx. 48%-lg solution of boron trifluoride in ether. The reaction mixture is stirred for 16 hours at RT, cooled to 10°C and added over 20 min. 276 ml of a 4N sodium hydroxide solution. The aqueous phase is separated and extracted with 2 x 400 ml methylene chloride. The combined organic extracts are washed with saline and dried over sodium sulfate. The title product is used further without further purification.

DC Bf(C) - 0.15;

IS (methylene chloride) (cm-<1>): 3370, 3020, 2920, 1640, 1605.

c) N-trifluoroacetyl-1-phenyl-3-butene-2(S)-amln:

Dissolved 1,210 ml of methylene chloride and 70 ml of pyridine are added

it dropwise to 11.9 g (81 mmol) of 1-phenyl-3-buten-2(S)-amine at 0<*>C, 17.0 ml (121 mmol) of trifluoroacetic acid. After stirring for 0.5 hours at 0°C, it is extracted twice with diluted HCl, water and salt solution. The aqueous phases are further washed twice with methylene chloride, dried over sodium sulfate and evaporated.

DC Rf(M) - 0.4.

d) 2( S )- fl,( S )-(trifluoroacetyl-amino)-2,- phenylethyl 1-oxirane: To a solution of 14.5 g (60 mmol) N-trifluoroacetyl-1-phenyl-3-butene- 2(S)-amine 1,600 ml of chloroform, 54.28 g (314 mmol) of m-chloroperbenzoic acid are added and the whole is stirred for 124 hours at RT. The reaction mixture is washed twice

with 10 µg sodium sulphite solution, twice with saturated sodium carbonate solution, water and saline. The aqueous phases are then extracted twice with methylene chloride, the combined organic phases are dried with sodium sulfate and evaporated to yield the title compound which is used without further purification in the next step.

DC Rf(N) - 0.6.

e) p-fluorophenylcarbaldehyde tert-butoxycarbonylhydrazone;

Analogously to example 4b), 32 g (242 mmol) of tert-butylcarbazate and 30 g (242 mmol) of p-fluorobenzaldehyde are reacted in 300 ml of ethanol at 80<*>C for 3 hours to the title compound, which crystallizes out on cooling and "dilution with water .

DC Rf(N) - 0.48; tRet(I) - 19.4 min.

f) tert-butyl-3-(p-fluorophenyl-methyl)-carbazate:

Analogously to example 4a), 55 g (231 mmol) of p-fluoro-phenylcarbaldehyde-tert-butoxycarbonylhydrazone in 500 ml of THF are hydrogenated with 5.5 g of palladium (5$) on charcoal to give the title compound.

<i>H-NMR (200 MHz, CD3OD): 7.35 (dd, 8 and 6 Hz, 2H),

7.05 (h, 8 Hz, 2H), 3.9 (s, 2H), 1.45 (s, 9H).

Example 17: N-morpholinocarbonyl-(L)-Val-[Phe10^ p-F )Phe]-Boe: A solution of 185 mg (0.80 mmol) N-morpholinocarbonyl-(L)-valine (preparation see example 7a), 270 mg (0.67 mmol) H-CPhe<NN>fp-FjPheD-Boc, 311 mg (0.70 mmol) BOP and 95 mg (0.70 mmol) HOBt are dissolved at RT in 6.8 ml NMM:DMF 0.3M and stirred for 15 hours at RT. The reaction mixture is evaporated under HV and the residue is distributed between 4 portions of methylene chloride, 2 portions of IM sodium carbonate solution, water and saline solution. The combined and dried phases over sodium sulfate are evaporated and purified by column chromatography (SiC>2, acetic acid ethyl ester).

DC Rf(0) - 038; tRet(J) " 21 »8 mln»

FAB-MS (M+H)<+> - 616.

The starting material is produced as follows:

a) H-[ PheNfl( p- F) Phe]- Boe:

At 70<*>C, a solution of 0.3 g (0.6 mmol) is added drop by drop

N-trifluoroacetyl-CPhe^p-DPhel-Boc (preparation see Example 16) 1 50 ml of methanol and under a ^-atmosphere, 15 ml of an IM aqueous solution of potassium carbonate and stir for 25 hours at this temperature. The reaction mixture is evaporated under HV, methylene chloride is added to the residue and washed twice with water and saline solution. The aqueous phases are extracted twice with methylene chloride, the organic phases are dried with sodium sulfate and evaporated. The raw product is processed without further purification in the next step.

<t>get(I) - 16.2 min.

Example 18: N-morphol Inocarbonyl-(L )-Val- [Phe^p-F )Phe]«—

((D-Val)-Z:

To a solution of 86 mg (0.34 mmol) Z-(L)-Val and 160 mg (0.31 mmol) N-morpholinocarbonyl-(L)-Val-[Phe<NN>(p-F)Phe]-H 1

129 mg (0.34 mmol) of HBTU are added to 2.7 ml of NMM/CH3CN 0.25M (0.25M NMM 1 CH3CN). After 4 hours at RT, the whole is evaporated and the residue is distributed between 3 parts methylene chloride, 2 parts saturated sodium bicarbonate solution and saline solution. Drying the organic phases with sodium sulfate and evaporation gives the title compound, which after digestion from methylene chloride ether (1:1) is obtained pure.

DC Rf(P) - 0.4; tRet(I) " 22»4 min.;

FAB-MS (M+H)<+> - 749.

The starting material is produced as follows:

a) N-morpholInocarbonyl-(L)-Val-[PheNN(p-F)Phe]-H:

Dissolved in 105 ml of formic acid, 210 mg (0.34 mmol) of N-morpholinocarbonyl-flJ-Val-CPhe<N>^p-FjPheJ-Boc (Example 17) are stirred for 4 hours at RT. The whole is then evaporated, the residue is taken up in methylene chloride and the solution is washed with saturated sodium bicarbonate solution and saline solution. Extraction of the aqueous phases with 2 parts of methylene chloride, drying of the organic phases with sodium sulfate and evaporation gives the title compound which is used without further purification in the next step.

tRet(I) - 12.9.

Example 19: N-»orphol inocarbonyl - (L )-Val-[Phe10^ p-F )Phe] «—

((U-Val)-H:

At normal pressure, 160 mg (0.21 mmol) of N-morpholinocarbonyl-(L)-Val-[Phe<NN>(p-F)Phe]*-((L)-Val)-Z (Example 18) in 6 ml of ethanol hydrated with 40 mg 10 56—lg palladium-on-carbon. After filtration through Celite® (Diatomaceous earth, filter aid from Fluka, Buchs, Switzerland), evaporation and lyophilization from dioxane, the title compound is obtained.

<t>Ret(hydrochloride, I) - 13.4 min.;

FAB-MS (M+H)<+> - 615.

TCirnftmTv»! an: N-mor f ol lnokar bony 1 - (L) -Val - [ Phe10* (p-F )Phe] «—

((L )-Val M N-morphol inocarbonyl-Gly):

To a solution of 26.9 mg (0.143 mmol) N-morpholinocarbonyl -glyein and 80 mg (0.130 mmol) N-morpholinocarbonyl-(L)-Val-[PheNN(p-F)Phe]*-((L)-Val) -H in 1.1 ml of NMM/CH3CN 0.25M, add 54 mg (0.143 mmol) of HBTU and stir for 16 hours at RT. One evaporates and distributes the residue between 3 parts acetic acid ethyl ester, water, 2 parts saturated sodium bicarbonate solution, water and salt solution. Drying the organic phases with sodium sulfate and evaporation gives the title compound, which after dissolution in a little DMF and precipitation with DIPE precipitates pure.

tRet(J) - 15.1 min.; FAB-MS (M+H)<+> - 785.

The starting material is produced as follows:

a) N-morpholinocarbonyl-glycol-benzyl ester:

Analogous to example 7b), 7.69 g (22.8 mmol) glycine benzyl ester-4-toluenesulfonate and 2.8 g (19 mmol) (morpholinocarbonyl)chlorine are reacted with 1,118 ml methylene chloride and 9 ml (53 mmol) N-ethyldiisopropylamine 1 18 hours. The title compound precipitates out in pure form after extraction with methylene chloride and digestion from hexane.

tRet(I) - 11.6 min.

b) N-mother f ol inocarbonyl - gl. vc in:

Analogously to example 7a), 4.8 g (18.3 mmol) of N-morpholinocarbonyl-glycine-benzyl ester in 100 ml of acetic acid ethyl ester are hydrogenated with 1 g of 10 5É-ig palladium-on-carbon to the title compound.

% NMR (300 MHz, CDCl 3 ): 3.88 (s, 2H), 3.64 (s, 4H),

3.50 (s, 2H), 3.35 (s, 4H).

Example 21; Z-UJ-Val-CPhe^p-FjPheD-Boc:

To a solution of 335 mg (1.33 mmol) Z-(L)-Val and 448 mg (1.11 mmol) H-[Phe<NN>(p-F)Phe]-Boc (preparation see example 17a) 1 9 .4 ml NMM/CE3CN 0.25M (0.25M NMM in CH23CN) add 463 mg (1.22 mmol) HBTU. After stirring for 16 hours at RT, the whole is evaporated and the residue is distributed between 3 parts methylene chloride, 2 parts saturated sodium bicarbonate solution and salt solution. Drying the organic phases with sodium sulfate and evaporation gives the title compound, which is purified by column chromatography (S102, hexane-acetic acid ethyl ester 4:1 1:1).

<t>Ret*1) - 26.6 min.; FAB-MS (M+H)<+> - 637.

Example 22; Z-(L)-Val-[Phe^p-F)Phe]«-((L)-Val )-Boc;

Analogously to example 18, 165 mg (0.76 mmol) Boe-(L)-Val and 371 mg (0.69 mmol) Z-dO-Val-CPheN^p-FjPheD-H 1 6 ml NMM/CH3CN 0.25M are reacted with 289 mg (0.76 mmol) of HBTU to the title compound which crystallizes directly from the reaction solution and can thereby be filtered off.

<t>Ret^1) - 27.2 min.; FAB-MS (M+H)<+> - 736.

The starting material is produced as follows:

a) Z-(L)-Val-[Phe^(p-F)Phe]-H:

Analogous to example 18a), the protecting group is removed from

440 mg (0.69 mmol) of Z-(L)-Val-[Phe<NN>(p-F)Phe]-Boe with 212 ml of formic acid to the title compound.

tRet^) " 17»8 mln-

Example 23; Z-(L )-Val-[Phe101 (p-F)Phe]«-((L )-Val )-H:

Analogously to Example 18a), the protecting group is removed from 250 mg (0.34 mmol) of Z-(L)-Val-[Phe<NN>(p-F)Phe]-((L)-Val)-Boc (Example 22) with 50 ml of formic acid to the title compound.

<t>Ret(I) - 18.0 min.; FAB-MS (M+H)<+> - 636.

Example 24: Z-fLj-Val-CPhe^p-FjPheM(L)-Val)«-(¥-morpho-1Inocarbonyl-Gly);

Analogous to example 20, 32 mg (0.17 mmol) of N-morpholinocarbonylglycine (example 20b) and 99 mg (0.16 mmol) of Z-(L)-Val-[Phe<NN>(p-F)Phe]«- ((L)-Val)-H in 1.3 ml of NMM/CH3CN 0.25M with 65 mg (0.17 mmol) of HBTU to the title compound which crystallizes out directly from the reaction solution.

"<t>Ret^1) - 21.1 min.; FAB-MS (M+H)<+> » 806.

Example 25; Z-(L)-Asn-[PheIDJ(p-F)Phe]-Boe:

To a solution of 2.09 g (5.2 mmol) H-[Phe<NN>(p-F)Phe]-Boe (preparation see example 17a) 1 68 ml DMF and 2.7 ml (16 mmol) N-ethyl 3.0 g (7.8 mmol) of Z-(L)-asparagyl-p-nitrophenyl ester (Bachem, Bubendorf, Switzerland) are added to -dlisopropylamine. After 16 hours of stirring at RT, the mixture is evaporated under HV, the residue is taken up with 1 lot of methylene chloride (heavily soluble) and washed with 2 parts of 5 lb calcium carbonate solution. The aqueous phases are then extracted twice with plenty of methylene chloride, the combined organic phases are dried with sodium sulfate and evaporated. After dissolving the crude product 1 in a little methanol and precipitation by adding toluene at -20°C, the title compound is obtained.

<t>RetC1) " 21.2 min.

Example 26; H-tLj-Asn-CPhe^p-FjPhell-Boc:

Analogous to example 19, 0.40 g (0.61 mmol) of Z-(L)-An-[Phe<NN>(p-F)Phe]-Boc in 20 ml of methanol is hydrogenated to the title compound.

tRet(I) - 14.9 min.

Example 27: Quinoline-2-carbonyl-(L)-Asn-[Phe<Wf>i(p-F)Phe]-Boe: Analogous to example 17, 134 mg (0.78 mmol) of quinoline-2-carboxylic acid (Fluka, Buchs , Switzerland) in 4 mL NMM/DMF 0.3M with 344 mg (0.78 mmol) BOP, 105 mg (0.78 mmol) HOBT and 268 mg (0.52 mmol) H-(L)-Asn-[ Phe<NN>(p-F)Phe]-Boe. Since H-(L)-Asn-[Phe<NN>(p-F)Phe]-Boc is still present after 16 hours of stirring at RT according to HPLC, a further 299 mg of BOP, 70 mg of HOBT, 89 mg of quinaldic acid and 113 µl NMM. After a further 16 hours, it is all evaporated and the residue is distributed between 3 parts methylene chloride, 2 parts saturated sodium bicarbonate solution and salt solution. The combined organic phases are dried with sodium sulfate and evaporated. Dissolving the crude product in a little DMF, precipitation with DIPE and cooling further

-20*C gives the title compound.

<t>Rect*1) " 22»8 ">in.; FAB-MS (M+H)<+> - 673.

Example 28: Z-fLj-Asn-CPhe^p-FjPheM(L)-Val-Z:

88 mg (0.35 mmol) Z-(L)-Val 1 3.8 ml NMM/DMF 0.3M are activated with 153 mg (0.35 mmol) BOP and 47 mg (0.35 mmol) HOBT and after 15 my. 144 mg (0.23 mmol) of Z-(L)-Asn-[Phe<NN>(p-F)-Phe]-H*2HC1 is added. After stirring for 14 hours at RT, the reaction mixture is evaporated, the residue is dissolved in 2 ml methanol and distributed between 3 parts methylene chloride and 2 parts IM sodium carbonate solution, the organic phase is dried with sodium sulfate and evaporated. Repeated dissolution of the crude product 1 in a little DMF and precipitation with DIPE gives the title compound.

<t>Ret(I) - 22»2 min.; FAB-MS (M+H)<+> - 785.

The starting material is produced as follows:

a) Z-(L)- Asn-[ Phe^ tp- F) Phe]- H• 2HC1:

Under ^-atmosphere it becomes a solution of 150 mg

(0.23 mmol) Z-(L)-Asn-[Phe<NN>(p-F)Phe]-Boc (Example 25) in 1 ml dioxane added 2 ml HCl/dioxane 4N (Fluka, Buens,

Switzerland). After stirring for 1.5 hours at RT, the reaction mixture is lyophilized and the lyophilisate is immediately reacted further.

Example 29: Tr in fluoro acetyl-[Phe^C p-F ^Phe]«-( (L)-Val )-Z: Analogously to example 17, 239 mg (0.95 mmol) of Z-(L)-Val are reacted in 10, 5 ml NMM(DMF 0.4M with 421 mg (0.95 mmol) BOP, 129 mg (0.95 mmol) HOET and 0.3 g (0.63 mmol) N-trifluoroacetyl-CPhe^p-F)-Phe] -H for 15 hours. Column chromatography (SiO 2 , methylene chloride: ether 10:1) and precipitation from DMF solution with DIPE gives the title compound.

DC Rf(0) - 0.15; tRet(I) - 25.9 min.;

FAB-MS (M+H)<+> - 633.

The starting material is produced as follows:

a) N- trifluoroacetyl-[ Phe*^ p- F) Phe]- H:

At 0°C, 5 ml of trifluoroacetic acid is added to 0.20 g (0.40 mmol) of N-trifluoroacetyl-[he^p-F)Phe]-Boe (preparation see example 16) in 5 ml of methylene chloride. After 4 hours of stirring at 0<*>C and 2 hours at RT, the reaction mixture is evaporated. Lyophilization of the residue from dioxane gives the title compound which is used further without further purification.

tRetd) - 14-7 mln-

Example 30: Z-(L)-Asn-[PhefflIPhe]-Boc:

Analogous to example 25, 167 mg (0.34 mmol) of H-CPhe^Phe]-Boe are reacted in 3.6 ml of DMF and 0.18 ml (1 mmol) of N-ethyl-diisopropylamine with 0.20 g (0.52 mmol ) Z-(L)-asparagine p-nitrophenyl ester to the title compound which after column chromatography (SIO2, acetic acid ethyl ester) is obtained in pure form.

DC Rf(0) - 0.19; tRet(I) " 20.9 min.

The starting material is produced as follows:

a) N- trifluoroacetyl-[ Phe^ Phel- Boe;

Analogous to example 16, 1.82 g (7.0 mmol) of 2(R)-[1*(S)-(trifluoroacetyl-amino)-2'-phenylethyl]-oxirane (example 16d) and 1.58 g (7 .1 mmol) tert-butyl-3-benzyl-carbazate ("J. Chem.", Perkln I, 1712 (1975)) 1 15 ml methanol 1 bomb tube to the title compound which then Is isolated by column chromatography.

DC Rf(J) - 0.38; *Correct(J) " 24»5 min«

b) H-CPhe^Phel-Boc:

Analogous to example 17a), 258 mg (0.53 mmol) of N-trifluoroacetyl-CPhe^Phej-Boc in 60 ml of methanol are reacted with 10.7 ml of 1M potassium carbonate solution to the title compound.

Example 31: Z-(L)-Yal-[(p-F)PheliN(p-F)Phe]-Boe:

Analogously to example 21, 18 mg (0.070 mmol) Z-(L)-Val and 27 mg (0.064 mmol) H-[(p-F)Phe<NN>(p-F)Phe]-Boc are reacted in 0.6 ml NMM/CH3CN 0 .25M with 26.6 mg (0.070 mmol) of HBTU to the title compound which is purified by dissolving in a little methylene chloride and precipitating with DIPE.

FAB-MS (M+H)<+> - 655.

The starting material is produced as follows:

a) N-Boc-(p-fluorophenvlalanln):

In 0.4 l of dioxane:water 1:1, 20 g (109 mmol) of p-fluoro-phenylalanine (Fluka, Buchs, Switzerland) are reacted with 35.5 g (163 mmol) of Boc anhydride and 150 g (1.09 moles) of potassium carbonate. After 4 hours, the reaction mixture is acidified with citric acid solution and extracted with 3 parts ethyl acetate. The organic phases are washed with 10 5t sulfuric acid, water and salt solution, dried with sodium sulfate and evaporated. Dissolving the residue in a little methylene chloride and recrystallization by adding hexane gives the title compound.

<t>Ret^1) " 16.9 min.

b) N-Boc-fp-fluorophenvlalannol):

At -5*C to -10*C it becomes a solution of 17.9 g (63 mmol) N-Boc-(p-fluorophenylalanine) in 73 ml abs. THF added 9.66 ml (69 mmol) of triethylamine, after which it is added dropwise to a solution of 9.05 ml (69 mmol) of chloroformate isobutyl ester in 44 ml of abs. THF. After one hour of stirring at RT, the formed precipitate is sucked off. The filtrate is added dropwise while cooling to 4.77 g (126 mmol) of sodium borohydride in 28 ml of water. After 4 hours of stirring at RT, the whole is made acidic with 10% sulfuric acid, the THF is partially evaporated from 1 in RV and the residue is distributed between 3 parts acetic acid ethyl ester, 2 parts 2N sodium hydroxide solution, water, saturated sodium hydrogen carbonate solution and saline solution. The organic phase dried with sodium sulfate and evaporated gives the title compound after dissolving 1 in a little methylene chloride and crystallization by adding hexane. DC Rf(N) - 0.36; tRetd) " 16»8 min.; <i>H-NMR (200 MHz, CD30D): 7.24 (dd, 8 and 5 Hz, 2H), 6.98 (t, 8 Hz, 2H), 3, 73 (m, 1H), 3.47 (d, 5 Hz, 2H), 2.88 (dd, 13 and 6 Hz, 1H), 2.62 (dd, 13 and -8 Hz, 1H), 1, 36 (p, 9H).

c) N-Boc-(p-fluorophenylalaninal):

Under ^-atmosphere one drops to a cooled to -60*C

solution of 4.0 ml (46.8 mmol) oxalyl chloride 1 44 ml methylene chloride 1 4.44 ml (62.4 mmol) DMSO dissolved in 76 ml methylene chloride. After 15 min. you then add to it

clear reaction solution 8.4 g (31.2 mmol) N-Boc-(p-fluorophenylalanol) as a solution 1,185 ml methylene chloride:THF 1:1 (-» precipitation) and stirring for a further 25 min. 17.3 ml (124.8 mmol) of triethylamine dissolved in 1 38 ml of methylene chloride are then added. After 30 min. while stirring, 278 ml of a 20% calcium hydrogen sulphate solution is added drop by drop, followed by 220 ml of hexane. The whole is heated at RT, the aqueous phase is separated and extracted with 2 parts of ether. The organic phases give after washing with saturated

sodium bicarbonate solution, water and salt solution, drying over sodium sulfate and evaporation, the title compound which is used further in the next step without further purification.

<*>E-NMR (200 MHz, CDC13): 9.63 (s, 1H), 6.9-7.2 (2m, 4H), 5.04 (m, 1H), 4.42 (m, 1E), 3.10 (m, 2H), 1.43 (s, 9H).

d) N-3(S)-(Boc-amino)-2(R.S)-hydroxy-4-(p-fluorophenyl)-1-trimethylbutane: Analogous to example 16a) 1.63 g (67 mmol) magnesium in 33 ml abs. ether with 8.3 ml (60 mmol) of chloromethyltrimethylsilane to a Grignard compound which, after reaction with 13 mmol of N-Boc-(p-fluorophenylalaninal), extraction and

column crown radiography (SIO 2 , hexane:ethyl acetate 5:1 -» 4:1) gives the title compound as a diastereomer mixture.

DC Rf(L) - 0.32; tRet(I) - 24.9 min.(22*)/25.5 min.(78*);

FAB-MS (M+E)<+> - 356.

e) 1-(p-fluorophenyl)-3-butene-2(S)-amln:

Analogously to example 16b), 1.1 g (3.1 mmol) of N-3(S)-(Boc-amino)-2(R,S)-hydroxy-4-(p-fluorophenyl)-1-trimethyl are reacted silyl-butane in 22 ml of methylene chloride with 1.9 ml (15.5 mmol) of an approx. 48 5Ég solution of boron trifluoride in ether to the title compound.

^H-NMR (300 MHz, CDCl 3 ): 7.2-7.10 and 7.05-6.9 (2m, each 2H), 5.9-5.8 (m, 1H), 5.2- 5.0 (m, 2H), 3.57 (m, 1H), 2.79 (dd, 12 and 6 Hz, 1H), 2.62 (dd, 12 and 8 Hz, 1H), 1.7 ( sb, 2H).

f) N-trifluoroacetvl-1-(p-fluorophenyl)-3-butene-2(S)-amln: Analogous to example 16c) 364 mg (2.2 mmol) of 1-(p-fluorophenyl)-3-butene- 2(S)-amine in 1.8 ml of methylene chloride and 5.4 ml of pyridine with 460 µl (3.3 mmol) of trifluoroacetic acid to the title compound which is obtained in pure form after digestion in hexane.

DC Rf(F) - 0.58; MS (M)<+> - 261.

g) 2(RI-T!'(S)-(trifluoroacetyl-amino)-2,-(p-fluorophenyl)ethyl-oxilran: Analogous to example 16d) 359 mg (1.37 mmol) of N-trifluoroacetyl-1- (p-fluorophenyl)-3-buten-2(S)-amine in 9 ml of chloroform with 1.18 g (6.87 mmol) of m-chloroperbenzoic acid to the title mixture.

DC Rf(R) - 0.45.

h) N- trifluoroacetyl-[( p- FJPhe0( p- F) Phe]- Boe:

Analogously to example 16), 415 mg (1.49 mmol) of 2(R)-[1 * (S)-(trifluoroacetyl-amino)-2'-(p.-fluorophenyl)ethyl]-oxirane and 377 mg ( 1.57 mmol) of tert-butyl-3-(p-fluorophenyl-methyl)-carbazate in 9 ml of methanol to the title compound.

DC Rf(S) - 0.53; FAB-MS (M+H)<+> - 518;

^H-NMR (300 MHz, CD3OD): 7.4-7.3 and 7.3-7.2 (2m, each 2H), 7.05-6.9 (m, 4H), 4.23 ( m, 1H), 3.90-3.65 (m, 3H), 3.03-2.78 and 2.74-2.60 (2m, each 2E), 1.30 (s, 9H). 1) H- C ( p- F iPhe^ tp- F ) Phe] - Boe;

Analogously to example 17a), 285 mg (0.55 mmol) of N-trifluoroacetyl-Cfp-FjPhe^p-FjPheJ-Boc are reacted in 45 ml of methanol with 14 ml of 1M potassium carbonate solution to the title compound.

tjjg-td) - 16.4 min.

Example 32: Z-(L)-Val-[(p-FjPhe10* (p-F)Phe]-H:

Analogously to example 18a), the protecting group is removed from 215 mg (0.33 mmol) of Z-(L)-Val-[(p-FjPhe<NN>fp-FiPhe]-Boe with 100 ml of formic acid to give the title compound).

FAB-MS (M+H)<+> - 555.

Example 33: Z-(L )-Val-[ (p-F )PheNN( p-F )Phe]«-(N-(N-(2-pyr i dy Ime tyl )-N-methyl-aminocarbonyl )-(L)- Val): Analogous to example 18, 23.6 mg (0.089 mmol) of N-(N-(2-pyridylmethyl)-N-methyl-aminocarbonyl)-(L)-valine are reacted (preparation see EP 402646 A1, 19 December 1990) and 45 mg (0.081 mmol) Z-(L)-Val-[(p-F)Phe<NN>(p-F)Phe]-H with 33.8 mg (0.089 mmol) HBTU in 0.76 ml NMM/CH3CN 0.25M to the title compound which is then recrystallized from DMF(DIPE).

DC Rf(0) - 0.39; FAB-MS (M+H)<+> - 802.

Example 34; Z-(L)-Val-[(p-F)Phe<NN>(p-F)Phe]«-(N-(2(S,S)-carbamoyl-3-phenyl-proplonyl )-(L)-Val): Analogous to example 18, 26.0 mg (0.089 mmol) of N-(2(H,S)-carbamoyl-3-phenyl-proplonyl)-(L)-valln (preparation: "Synth., Struct., Funct.", "Proe. Am. Pept. Symp.", 7., 85,

(1981)) and 45 mg (0.081 mmol) of Z-(L)-Val-[(p-F)Phe<NN>(p-F)-Phe]-E (Example 32) reacted with 33.8 mg (0.089 mmol) of HBTU 1 0.76 ml NMM/CH 3 CN 0.25M to the title compound which was then recrystallized from DMF/DIPE.

Rf(P) - 0.64; FAB-MS (M+H)<+> - 829.

Example 35: Acetyl-Val- [Phe^Phe]«-(N-acetyl-Val):

Analogous to example 7, the title compound is obtained from 100 mg (0.25 mmol) H-CPhe<NNp>hel-H-SHCl from example 2a), 121 mg (0.76 mmol) N-acetyl-(L)-valine, 288 mg (0.76 mmol) HBTU and 0.211 ml (1.52 mmol) triethylamine in DMF after lyophilization from dioxane.

FAB-MS (M+H)<+> - 568; tRet(<:>) " 15»° min.;

Rf(B ) - 0.46.

Example 361 Z-(D)-Val-[PheMfPhe]«-((D)-Val )-Z:

Analogous to example 2, the title compound is obtained from 50 mg (0.123 mmol) H-[Phe^Phe]-H*3HC1 from example 2a), 95 mg (0.38 mmol) Z-(D)-valine, 168 mg (0, 38 mmol) BOP, 51 mg (0.38 mmol) HOBt and 2.53 ml 0.3 M NMM in DMF after lyophilization from dioxane.

FAB-MS (M+H)<+> - 752; tRet(I) - 26.4 min.;

Rf(H) - 0.21.

Example 37: Quinoline-2-carbonyl-Val-[Phe^Phe]«-( N-quinoline-2-carbonyl-Val): 45 mg (0.53 mmol) of N-(quinoline-2-carbonyl)- (L)-valine, 235 mg (0.53 mmol) BOP and 72 mg (0.53 mmol) EOBt in 3.5 ml of a 0.3 M solution of NMM in DMF, add after 10 min. 70 mg (0.18 mmol) H-CPhe^Phe]-H*HCl (Example 2a) and stir for 5 hours at RT under nitrogen atmosphere. The reaction mixture is evaporated, the residue is dissolved in 1 methylene chloride and washed twice with saturated sodium bicarbonate solution, once with 10% sulfuric acid and once again with saturated sodium bicarbonate solution. The organic phases are filtered through water, evaporated and the residue is precipitated twice from methylene chloride:methanol by adding DIPE. After lyophilization from dioxane, the title compound is obtained as a white solid (mixture of two diastereomers detectable in HPLC).

FAB-MS (M+H)<+> - 794; *Ret(A) - 29.1 and 29.3 min.

Rf(B ) - 0.81.

a) N-(choline-2-carbonyl)-(L)-valyl;

To a solution of 2.5 g (14.5 mmol) of (L)-valyl-tert-butyl ester and 2.5 g (14.5 mmol) of chloroline-2-carboxylic acid in 100 ml of methylene chloride:THF (10:1) 3.28 g (15.9 mmol) of N,N-dlcyclohexylcarbodillmld and 2.0 ml (14.5 mmol) of triethylamine are added and the whole is stirred for 18 hours at RT. The reaction mixture is cooled to -18°C and organic matter is filtered off. The filtrate is evaporated, the residue is dissolved in 1 methylene chloride and washed once with sodium bicarbonate solution and once with water. The organic phases are filtered through water, evaporated and after chromatographic purification on silica gel with hexane:ethyl acetic acid ester (2:1) gives the desired N-(choline-2-carbonyl)-(L)-valyl-tert-butyl ester. 2.59 g (12.2 mmol) of this is added for 4 hours at RT in methylene chloride: TFA (1:1). After evaporation, the residue is purified by chromatography on silica gel with hexane:acetic acid (2:1). The product-containing fractions are evaporated, redissolved in 1 methylene chloride and transferred by washing with 1N sodium hydroxide solution and 1N hydrochloric acid to the hydrochloride of the title compound.

<*>H-NMR (200 MHz, CD30D): 1.05 and 1.07 (2d, J-6Hz, 6H), 2.40 (m, 1H), 4.65 (m, 1H), 7, 70 (m, 1H),

7.85 (m, 1H), 8.00 (dxd, 1H), 8.20 (m, 2H),

8.48 (d, 1H).

Example 38; Acetyl-(L)-Val-[PheliNCha]«-(N-acetyl-(L)-Val): Analogous to example 37, the title compound is obtained from 160 mg (0.40 mmol) of H-CPheNNchal-H* 3BX1 from example 10a ), 190 mg (1.19 mmol) N-acetyl-(L)-valine, 525 mg (1.19 mmol) BOP, 160 mg (1.19 mmol) HOBt and 7.9 ml 0.3 M NMM in DMF , after precipitation from chloroform:methanol with DIPE and lyophilization from dioxane.

FAB-MS (M+H)<+> - 574; tRet(<I>) - 18.1 min.;

Rf(B) - 0.30.

Example 39; N-(3-pyridylacetyl)-(L)-Val-[Phe^Cha]•-(N-(3-pyridylacetyl )-(L)-Val )• 3HC1: Analogous to example 7, the title compound is obtained from 100 mg (0 .25 mmol) H-[Phe^Cha]-H*3EC1 from Example 10a), 358 mg (1.52 mmol) N-(3-pyridylacetyl)-(L)-valine from Example 9a), 675 mg (1 .52 mmol) HBTtT and 0.316 ml (2.28 mmol) triethylamine 1 DMF after chromatographic purification from silica gel with methylene chloride:methanol (15:1) and lyophilization of the product-containing fractions from dioxane.

FAB-MS (M+H)<+> - 728; tRet(I) - 11.3 min.;

Rf(U) - 0.21.

Example 40: Acetyl-Ile-CPhe^CbÅ^N-acetyl-Ile):

Analogous to example 37, the title compound is obtained from 160 mg (0.40 mmol) H-[Phe^Cha]-H*3HC1 from example 10a), 2.06 mg (1.19 mmol) N-acetyl-(L)-isoleucine , 525 mg (1.19 mmol) BOP, 160 mg (1.19 mmol) HOBt and 7.9 ml 0.3 M NMM 1 DMF after precipitation from methylene chloride:methanol after addition of DIPE and lyophilization from dioxane:tert-butanol ( mixture of 2 1 HPLC detectable diastereomers).

FAB-MS (M+H)<+> - 602; tRet(I) - 20 »4 °« 20»7 min.;

Rf(D) - 0.33.

Example 41: Ti omor f ol inocarbonyl - (L) -Val - [ Phe^Cha] «—

(H-thiomorpholInocarbonyl-(L)-Val):

Analogous to example 6, starting from 70 mg (0.12 mmol) H-(L-Val )-[PheNNCha]«-(N-(L)-Val )-H'3HCl from example 14, 58 mg (0.35 mmol) (4-thiomorpholylcarbonyl) chloride from example 6a) and 0.127 ml triethylamine in 2 ml DMF the title compound after chromatographic purification on silica gel with methylene chloride:methanol (95:5) and lyophilization of the product-containing fractions from dioxane.

FAB-MS (M+H)<+> - 748; tRet(<I>) - 24.0 min.;

Rf(B) - 0.70.

Example 42: Z-(L)-Glu-[PheliN(p-F)Phe]«-((L)-Glu)-Z:

A solution of 130 mg (0.14 mmol) Z-(L)-Glu(0-tert-butyl MPheNNfp-F )Phe]«-( (L)-Glu(O-tert-butyl) )-Z is stirred [(Glu(0-tert-butyl) here means the residue of glutamic acid esterified on the ir -carboxy group with a tert-butyl residue] in 80 ml methylene chloride:TFA (1:1) for 3 hours at RT. The solvent evaporated under reduced pressure and the residue precipitated from methylene chloride after addition of DIPE. The title compound is obtained after lyophilization from dioxane:tert-butanol.

FAB-MS (M+H)<+> - 830; tRet(<J>) " 19»6 min.;

Rf(B) - 0.32.

a) Z-( L)- Glu( 0- tert-butyl)- CPhe^ Cp- F) Phe] «-( ( L)- Glu( 0- tert-- butyin- Z: Analogous to example 37, the title compound is obtained from 100 mg (0.24 mmol) H-CPhe^p-DPheil-H-SHCl, 245 mg (0.73 mmol) Z-(L)-glutamic acid tert-butyl ester, 321 mg (0.73 mmol) BOP, 98 mg (0.73 mmol) HOBt and 4.8 ml 0.3 M NMM 1 DMF after chromatographic purification on silica gel with methylene chloride:ether (1:1).

<t>Ret*1) - 30'2 min.; Rf(H) - 0.17.

b) H-[ Phe^( p- F) Phe]- H- 3HC1:

Analogous to example 2a), the title compound is obtained by

start from 1.77 g (3.51 mmol) of Boc-CPhe<NN>fp-F)Phe]-Boe after lyophil separation.

FAB-MS (M+H)<+> - 304; Rf(K) - 0.19.

c) Boe-[ Pheyy( p- F) Phe]- Boe:

Analogous to example 1, the title connection is achieved by walking

from 2.0 g (7.60 mmol) (2R )-[1'(S)-Boc-amino-2*-phenylethyl]oxirane and 2.17 g (9.04 mmol)_tert-butyl-3- (4-Fluorophenyl-methyl)-carbazate from example 16f) after chromatographic purification on silica gel with hexane:acetic acid ethyl ester (2:1).

FAB-MS (M+H)<+> - 504; "tRet(I) - 26.2 min.;

Rf(F) - 0.26.

Example 43; N-(2-pyridylmethyl)-N-methyl-aminocarbonyl-(L)-Val-[Phe^p-F)PheMM-(N-(2-pyridylmethyl)-¥-■ethyl-aminocarbonyl)-(L)-Val ): Analogous to example 37, the title compound is obtained from 70 mg (0.17 mmol) H-[PheNN(p-F)Phe]-H-3HCl from example 42b), 135 mg (0.51 mmol) N-(N-(2 -pyridylmethyl)-N-methyl-aminocarbonyl)-(L)-valine (preparation as in EP 0 402 646 A1), 225 mg (0.51 mmol) BOP, 69 mg (0.51 mmol) HOBt and 3.4 ml 0.3M NMM in DMF, after chromatograph! on silica gel with methylene chloride:methanol (15:1) and lyophilising the product-containing fractions from dioxane.

FAB-MS (M+H)<+> - 798; tRet(<I>V) - 35 min.;

Rf(U) - 0.21.

Example 44: N-(3-(tetrazol-1-yl)-proplonyl)-Val-[Phe*O* (p-F)-Phe]«-(N-(3-tetrazol-1-yl)-propionyl)- Val): Analogous to example 37, the title compound is obtained from 100 mg (0.24 mmol) H-CPhe<N>^p-FjPhel-H-SHCl (from example 42b), 146

mg (0.61 mmol) N-(3-(tetrazol-1-yl)-propionyl)-(L)-valine, 268 mg (0.61 mmol) BOP, 82 mg (0.61 mmol) HOBt and 4 ml of 0.3M NMM in DMF, after precipitation from methylene chloride by addition of DIPE and lyophilization from dioxane (4 diastereomers can be recognized

by HPLC).

FAB-MS (M+H)<+> - 750;

tRet(III) - 30.8; 31.4; 32.4 and 32.8 min.;

Rf(K) - 0.5.

Teirnft^pftf ddn• h-(3-(tetrazol-l-yl)-propionyl)-(L)-valine: Analogous to example 9b) one obtains, starting from 4 g (16.4 mmol) (L) -valine benzyl ester*HCl, 2.1 g (14.9 mol) 3-(tetra-zol-1-yl)-propionic acid (preparation: US-PS 4 794 109), 2.4 ml cyanophosphonic acid diethyl ester and 4 .4 ml of triethylamine in DMF, after chromatographic purification on silica gel with methylene chloride:methanol (30:1), N-(3-(tetrazol-1-yl)-propionyl)-(L)-vaine benzyl ester. 2.66 g (8.03 mmol) of this compound is hydrated in methanol:water (9:1) in the presence of 530 mg 10 *- ig palladium-on-charcoal at 1 atm. hydrogen pressure and gives after precipitation from the methanol/DIPE title compound.

^H-NMR (200 MHz, CD30D): 0.9 (d, J-7Hz, 6H), 2.1 (m, 1H),

2.95 (m, 2H), 4.29 (d, J-6Hz, 1H), 4.78 (1, 2H),

9.15 (p, 1H).

Example 45: Z-(L)-Val-[Phe<10>^p-F)Phe]-((L)-Val)-Z:

Analogously to example 37, the title compound is obtained from 100 mg (0.24 mmol) H-[Phe^(p—F)Phe]-H* 3HC1 (from example 42b), 182 mg (0.38 mmol) Z-(L) -valine, 321 mg (0.73 mmol) BOP, 98 mg (0.73 mmol) HOBt and 4.8 ml 0.3 M NMM in DMF after precipitation from methylene chloride by addition of DIPE and lyophilization from dioxane.

FAB-MS (M+H)<+> - 770; "tRet(I) - 26.3 min.;

Rf(H) - 0.25.

Example 46: Acetyl-Val-[Phe^p-F)Phe]*-(tf-acetyl-Val): Analogous to example 37, the title compound is obtained from 80 mg (0.19 mmol) H-[Phe^(p—F)Phe ]-H*3HC1 from Example 41b), 124 mg (0.78 mmol) N-acetyl-(L)-valine, 344 mg (0.78 mmol) BOP, 105 mg (0.76 mmol) HOBt and 4, 5 ml of 0.3 M NMM in DMF after reprecipitation twice from methylene chloride and methanol by adding DIPE and lyophils from dioxane:tert-butanol.

FAB-MS (M+H)<+> - 586; tRet(<I>) " 15»8 »in.;

Rf(E) - 0.32.

Example 47: Acetyl-Val-CPhe^p-CftjPheMN-acetyl-Val): Analogous to Example 37, the title compound is obtained from 80 mg (0.19 mmol) H-CPhe<NN>fp-ClOPheD-H-SHCl, 124 mg (0 .78 mmol) N-acetyl-(L)-vallin, 344 mg (0.78 mmol) BOP, 105 mg (0.78 mmol) HOBt and 4.5 ml 0.3 M NMM in DMF after precipitation from methylene chloride: methanol by adding DIPE and lyophils from dioxane as a mixture of two diastereomers detectable by HPLC.

FAB-MS (M+H)<+> - 593; tRet(I) - 14.4 and 14.6 min.;

Rf(D) - 0.39.

a) H-[ PheNK( p- CN) Phe]- H- 3HC1:

Analogous to example 2a), the title compound is obtained by

starting from 2.69 g (5.27 mmol) Boe-[Phe<NN>(p-CN)Phe]-Boe after lyophilization.

FAB-MS (M+H)<+> - 311; Rf(K) - 0.16.

b) Boe-[ PheNN( p- CN) Phe]- Boe:

Analogous to example 1, the title connection is achieved by walking

from 2.0 g (7.60 mmol) (2R)-[l<*>(S)-Boc-amino-2'-phenylethyl]oxirane and 1.87 g (7.6 mmol) tert-butyl- 3-(4-cyanophenyl-methyl)-carbazate after crystallization from methanol: DIPE.

FAB-MS (M+H)<+> - 511; tRet(I) " 25 min.;

Rf(Y) - 0.19.

c) tert-butyl-3-(4-cynophenyl-methyl)-carbazate:

Analogously to example 4b), 10 g (76.3 mmol) of 4-cyanobenzaldehyde and 10 g (76.3 mmol) of tert-butylcarbazate 1 ethanol are converted to 4-cyanophenylcarbaldehyde-tert-butoxycarbonylhydrazone. 11.1 g of this is hydrated in 150 ml THF 1 in the presence of 2 10 #-ig palladium-on-charcoal at 2 atm. hydrogen pressure and gives the title compound.

<i>H-NMR (200 MHz, CDC13): 7.65 (d, J-8Hz, 2H), 7.45 (d,

J-8Hz, 2H), 6.08 (s, br, 1H), 4.3 (s, br, 1H), 4.02 (s, 2H), 1.45 (s, 9H).

Example 48: Z-(L)-Val-[Pheini"(p-CH)Phe]«-((L)-Val-Z:

Analogously to example 37, the title compound is obtained from 70 mg (0.17 mmo 1) H-[Phe<NN>(p-CN)Phe]-H-3HCl (from example 47a), 125 mg (0.5 mmol) Z- (L)-vallin, 221 mg (0.5 mmol) BOP, 68 mg (0.5 mmol) HOBt and 3.33 ml 0.3 M NMM in DMF, after precipitation from methylene chloride by addition of hexane and subsequent lyophilization from dioxane .

FAB-MS (M+H)<+> - 777; tRet(<I>) - 25.3 min.;

Rf(D) - 0.69.

Example 49: Z-fLj-Ile-CPhe^LeuM(L)-Ile)-Z:

Analogous to example 37, the title compound is obtained from 70 mg (0.19 mmol) H-[Phe^Leu]-H*3HC1 (from example 13a), 154 mg (0.58 mmol) Z-(L)-isoleucine, 257 mg (a.58 mmol) BOP, 79 mg (0.58 mmol) HOBt and 3.88 ml 0.3 M NMM in DMF, after chromatography on silica gel with methylene chloride:ether (3:1) and precipitation of the product-containing fractions from methylene chloride: DIPE and lyophilization from dioxane.

FAB-MS (M+H)<+> - 746; tRet(<I>) - 28.2 min.;

Rf(H) - 0.39.

Tgifa^mp«»l Kn: Isobutoxycarbonyl-(L )-¥al-[Phe^Leu]«-(H-i8butoxycarbonyl-(L)-Val): Analogous to example 37, the title compound is obtained from 70 mg (0.19 mmol ) H-[Phe^Leu]-H*3HC1 (from Example 13a), 130 mg (0.58 mmol) N-(isobutoxycarbonyl)-(L)-valine, 256 mg -.58 mmol) BOP, 78 mg ( 0.58 mmol) HOBt and 3.9 ml 0.3 M NMM 1 DMF, after chromatography on silica gel with methylene chloride:ether (1:1) and lyophilization of the product-containing fractions from dioxane.

FAB-MS (M+H)<+> - 650; tRet(I) - 26.4 min.;

Rf(H) - 0.38.

a) N-(isobutoxycarbonyl)-(L)-valine:

11.2 ml (85.3 mmol) isobutyl chloroform is added to a solution of 10 g (85.3 mmol) (L)-valln 1 in 100 ml 2N caustic soda and stirred at RT 1 for 18 hours. The reaction solution is washed with methylene chloride, acidified with 4N hydrochloric acid and extracted with methylene chloride. The organic extracts are washed with saline, filtered through water and, after evaporation, give the title compound as a colorless resin. <i>H-NMR (200 MHz, CD30D): 0.59 (m, 12H), 1.9 (m, 1H), 2.15 (m, 1H), 3.85 (d, J-7Hz, 2H), 4.05 (d wide, 1H). Example 51; N-(3-(tetrazol-1-yl)-proplonyl)-(L)-Val- [PheNNLeu]«-(N-3-(tetrazol-1-yl)-pyropionyl - (L )-Val): Analogous to example 37, the title compound is obtained from 150 mg (0.42 mmol) H-CPhe^Leu]-H * 3HCl (from Example 13a), 251 mg (1.04 mmol) N-(3-(tetrazol-l-yl-propionyl)-(L)-valine from Example 44a), 460 mg (1.04 mmol) BOP .

FAB-MS (M+H)<+> - 689; tRet(<I>) - 14.7 min.;

Rf(K) - 0.36.

Example 52: Acetyl - Val - [ Phe^Leu]«-( N-acetyl - Val):

Analogous to example 37, the title compound is obtained from 70 mg (0.19 mmol) H-CPhe^LeuD-H-SHCl (from example 13a), 184 mg (1.16 mmol) N-acetyl-(L)-valine, 512 mg (1.16 mmol) BOP, 156 mg (1.16 mmol) HOBt and 7.8 ml 0.3 M NMM 1 DMF, after precipitation from methylene chloride:methanol by addition of DIPE and lyophilization from dioxane:tert-butanol:water ( 2 diastereomers are recognizable according to HPLC).

FAB-MS (M+H)<+> - 534; tRet(I) " 14»7 °« 15min.;

Rf(D ) - 0.35.

Example 53; (D-Val-CPhe^Leu]^ (L)-Val )-Boc:

Analogous to example 7, the title compound is obtained from 300 mg (0.83 mmol) H-CPhe<N>^Leul-H-3HC1 (from example 13a), 722 mg (3.33 mmol) Boc-(L )-valine, 1.262 g (3.33 mmol) HBTU and 0.927 ml (6.66 mmol) triethylamine in DMF, after chromatographic purification on silica gel with methylene chloride:ether (1:1), precipitation of product-containing fractions and lyophil separation from dioxane.

FAB-MS (M+H)<+> - 650; tRet(I) - 26.3 min.;

R f (H) - 0.64.

Example 54: H-(L)-Val-[Phe^I*u]«-((L)-Yal )-H'3HCl:

Analogous to example 5, the title compound is obtained from 396 mg (0.61 mmol) Boc-(L )-Val-[PheNNLeu]*-((L )-Val )-Boc from example 53 and 10 ml of 4N hydrogen chloride in dioxane, after lyophilization of the reaction solution.

FAB-MS (M+H)<+> - 450; <t>Ret(II) - 2*-1 min.;

Rf(K) - 0.25.

Example 55: N-thiomorphol inocarbonyl-(L )-Val- [Phe^-Leu]«-(N-thiomorpholinocarbonyl-(L)-Val): Analogous to example 6, the title compound is obtained by starting from 100 mg (0 .16 mmol) H-(L)-Val-[PheNNLeu]«-(L)-Val-H'3HCl, 78.5 mg (0.47 mmol) (4-thiomorpholinylcarbonyl) chloride from Example 6a) and 0.174 ml triethylamine in DMF after chromatographic purification on silica gel with methylene chloride:methanol (95:5), precipitation of the product-containing fractions from methylene chloride:hexane and lyophilization from dioxane, in the form of an amorphous solid.

FAB-MS (M+H)<+> - 708; tRet(I) - 21.4 min.;

Rf(E) - 0.45.

Example 56: 2 (E,S)-tetrahydrofury1-methoxycarbonyl-(L)-Val-[Cna^Leu]«-(H-2(B,S)-tetrahydrofury1-methoxycarbonyl-(L)-Val): Analogous example 37 the title compound is obtained from 80 mg (0.22 mmol) H—[Cha^Leu]-H*3HC1, 160 mg (0.65 mmol) N-(2(R,S)-tetrahydrofuryl-methoxycarbonyl)-(L )-valln, 289 mg (0.65 mmol) BOP, 88 mg (0.65 mmol) HOBt and 4.35 ml 0.3 M NMM 1 DMF, after chromatographic purification on silica gel with ethyl acetate and lyophilization of the product-containing fractions from dioxane .

FAB-MS (M+H)<+> - 712; *Ret(I) " 22 •4 min.;

Rf(E) - 0.21.

a) H-[ ChaNNLeu]- H• 3HC1:

Analogous to example 5, the title compound is obtained from 150

mg (0.33 mmol) Boc-CCha^Leu]-Boe and 10 ml of 4N hydrogen chloride in dioxane after lyophilization of the reaction solution, in an amount of 100 mg corresponding to 83$.

Rf(K) - 0.26.

b) Boc-rCha^ Leul-Boc:

A solution of 200 mg (0.24 mmol) Boc-CPhe^Leu]-Boe

(Example 12) in 15 ml of methanol, 1 is hydrated in the presence of 10 mg of Nlshlmura catalyst (Rh(III) and Pt(IV) oxide monohydrate, Degussa) at 1 atm. hydrogen pressure for 4 hours. The catalyst is filtered off, the solvent is evaporated completely and the title compound is obtained after crystallization from

methylene:hexane.

tRetd) " 26.7 min.; Rf(V) - 0.21.

c) N-f2(R.S)-tetrahydrofurvl- methoxycarbonvl) - (L)-valine: Analogously to example 50a) one obtains the title compound from 7

g (60 mmol) (L)-vallin and 9.8 g (60 mmol) 2(R,S)-tetrahydrofurylmethyl formate ("Hetercycles", 27, 1155 (1988)) 1,100 ml 2N caustic soda and 30 ml of dioxane as a mixture of two diastereomers.

<t>Ret(II) - 23.5 and 23.8 min.

Example 57; Z-Val-[Phe<NN>Leu]«-(»-( 3-(tetrazol-l-yl )-proplonyl)-Val): Analogous to Example 37, the title compound is obtained from 100 mg (0.21 mmol) of Z-( L)-Val-[Phe<NN>Leu]-H, 75 mg (0.31 mmol) N-(3-(tetrazol-1-yl)-propionyl)-(L)-valine from Example 44a), 137 mg (0.31 mmol) BOP, 42 mg (0.31 mmol) HOBt and 2 ml 0.3M NMM in DMF, after precipitation from methylene chloride:hexane and lyophilization from dioxane:tert-butanol (2 diastereomers can be recognized by

HPLC).

FAB-MS (M+H) + - 708; tRet^<1>) " 21-1 °8 21.1 min.;

Rf(D) - 0.45.

a) Z - ( L) - Val - [ Phe^ Leu] - H:

A solution of 250 mg (0.43 mmol) Z-(L)-Val-[Phe<NN>Leu]-Boe in 5 ml of formic acid is stirred for 7% hour at RT. After this time, no starting material can any longer be recognized by HPLC analysis (tRet(I) - 27.5 min.), and the reaction solution is evaporated. The residue is dissolved in chloroform and washed with saturated sodium bicarbonate solution'. The chloroform phase is filtered through water and gives the impure title compound after evaporation of the solvent.

<t>Ret^1) - 16>7 min.; Rf(K) - 0.21.

b) Z-(L)- Val- CPhe^ Leu]- Boe:

Analogous to example 37, the title compound is obtained from 230

mg (0.653 mmol) H-CPhe^Leu-Boc, 247 mg (0.98 mmol) Z-(L)-Valln, 434 mg (0.98 mmol) BOP, 133 mg (0.98 mmol) HOBt and 6 .5 ml of 0.3 M NMM 1 DMF, after precipitation from methylene chloride:

methanol by adding DIPE.

FAB-MS (M+H)<+> - 585; tRet(I) - 27.5 min.;

Rf(C) - 0.71.

c) H- rPhe^ LeuJ- Boc:

Analogous to example 17a), the title compound is obtained by

start from 1.27 g (2.84 mmol) N-trifluoroacet3rl-[Phe<NN>Leu]-Boc and 24 ml IN aqueous sodium carbonate solution 1 90 ml methanol, after which the title compound is precipitated from

methylene chloride by adding DIPE.

"tRet*1) " 14»9 min.; Rf(K) - 0.38.

d) N-trlfluoroacetyl-CPhe^Leul-Boc:

Analogous to example 16, one obtains by starting from 3 g (11.57

mmol) 2(R)-[1,(S)-(trifluoroacetyl-amino)-2'-phenylethyl]-oxirane from example 16d) and 2.3 g (12.15 mmol) tert-butyl -3-isobutyl- carbazate (preparation: "J. Chem. Soc.<H>, Perkin I, 1712 (1975)), the title compound after chromatographic purification on silica gel with methylene chloride:ether (20:1).

<t>Ret(I) " 24»7 min.; Rf(W) - 0.36.

Example 581 Acetyl-Val-[Phe^Leu]«-(»-(2(R,S)-carbamoyl-3-phenyl-proplonyl)-Val): Analogous to example 37, the title compound is obtained from 140 mg (0.3 mmol ) acetyl-(L)-Val-[Phe<NN>Leu]-H*2HCl, 132 mg (0.45 mmol) N-(2(R,S)-carbamoyl-3-phenyl-propionyl)-(L )-valln (Preparation: "Synth., Struct., Funct.", "Proe. Am. Pept. Symp.", 7,, 85, (1981)), 199 mg (0.45 mmol) BOP, 61 mg (0.45 mmol) HOBt and 3.5 ml 0.3 M NMM 1 DMF, after precipitation from methylene chloride: DIPE and lyophilization from dioxane (2 diastereomers can be recognized by HPLC).

FAB-MS (M+H)<+> - 667; tRetd) - 17»9 °S 18•4 min.;

Rf(D) - 0.33.

a) Acetyl- Val-[ Phe^ Leu]- H* 2HC1:

Analogous to example 2a), the title compound is obtained by

proceed from 230 mg (0.46 mmol) acetyl - (L) - Val - [ Phe^Leu] -Boe after lyofillserlng.

tRet(I) - 10.5 min.; Rf(D) - 0.38.

b) Acetyl - Val - [ Phe^ Leu] - Boe:

Analogous to example 37, the title connection is obtained by walking

from 250 mg (0.71 mmol) H-CPhe^Leu]-Boe from Example 57c), 170 mg (1.07 mmol) N-acetyl-(L)-valine, 471 mg (1.07 mmol) BOP , 144 mg (1.07 mmol) HOBt and 7.1 ml 0.3 M NMM 1 DMF after precipitation from methylene chloride by addition of DIPE and lyophilization from dioxane.

FAB-MS (M+H)<+> - 493; tRet(<I>) - 20.5 min.;

Rf(D) - 0.59.

Example 59: N-morphol inocarbonyl - (L) -Val - [Phe^Leu] ♦-( N-(3-(tetrazol-1-yl)-propionyl)-Val): Analogous to example 37, the title compound is obtained from 100 mg (0.19 mmol) N-morpholinocarbonyl-(L)-Val-[Phe<NN>Leu]-H-2HCl, 67 mg (0.38 mmol) N-(3-(tetrazol-l-yl)- propionyl)-(L)-valine from Example 44a), 124 mg (0.28 mmol) BOP, 38 mg (0.28 mol) HOBt and 2.1 ml 0.3 M NMM in DMF, after precipitation from methylene chloride by addition of DIPE and lyophilization from dioxane (2 diastereomers can be recognized by HPLC).

FAB-MS (M+H)<+> - 687; <t>Ret(<I>) " 15»2 °S 15.4 min.;

Rf(D) - 0.25.

a) N- mother f ol Inocarbonyl - ( L) - Val - [ Phe^ Leu] - H • 2HC1;

Analogous to example 37, the title connection is obtained by walking

from 279 mg (0.49 mmol) of N-morpholinocarbonyl-(L)-Val-[Phe^LeuJ-Boc after lyophilization.

FAB-MS (M+H)<+> - 464; tRet(11) - 30.3 min.;

Rf(D) - 0.46.

b) N-morphol inocarbonyl - ( L) - Val - [ Phe^ Leu] - Boe:

Analogous to example 37, the title compound is obtained by

start from 250 mg (0.71 mmol) H-CPhe^Leu]-Boe (from Example 57a), 265 mg (1.07 mmol) N-morpholinocarbonyl-(L)-valine from Example 7a), 471 mg ( 1.07 mmol) BOP, 144 mg (1.07 mmol) HOBt and 7.1 ml 0.3 M NMM in DMF, after precipitation from methylene chloride:hexane and lyophilization from dioxane.

FAB-MS (M+H)<+> - 564; tRet*1) - 21.5 min.;

Rf(K) - 0.69.

Example 60: N-trifluoroacetyl - [Phe^Leu]«-(N-(2 (R, S)-carbamoyl-3-phenyl-proplonyl)-(L)-Val): Analogous to example 37, one obtains the title compound starting from 136 mg (0.32 mmol) of N-trifluoroacetyl-CPhe^LeulH-2HCl, 142 mg (0.49 mmol) of N-(2(R,S)-carbamoyl-3-phenyl-proplonyl) -(L)-valine (Preparation: "Synth., Struct., Funct.", "Proe. Am. Pept. Symp. 7<tn>", 85 (1981)), 215 mg (0.49 mmol) BOP . dioxane:tert-butanol (2 diastereomers can be recognized by HPLC).

FAB-MS (M+H)<+> - 622; tRet^<1>) 21'6 °S 22»° min.;

Rf(K) - 0.26.

A) n- t r i f luoracetyl - [ Phe^ Leu] - H • 2HC1

Analogously to example 2a), the title compound is obtained by starting from 300 mg -.67 mmol) of N-trifluoroacetyl-[Phe^Leu]-Boe from example 57d) after lyophilization.

Rf(W) - < 0.1

Example 61: Z-(L )-Val-[Phe^Nle]«-(N-(2(R,S)-(N-(2-morpholino-ethyl)-carbamoyl)-3-methyl)-butyryl) : Analogous to example 37, the title compound is obtained by starting from 100 g (0.17 mmol) Z-(L)-Val-[Phe^Nle]-H*2HC1, 69 mg (0.27 mmol) 2(R, S)-(N-(2-morpholinoethyl)-carbamoyl)-3-methyl-butyric acid (isopropylmalonic acid-N-(2-morpholnoethyl)monoamld), 119 mg -.27 mmol) BOP, 36 mg (0.27 mmol) HOBt and 2.1 ml of 0.3M NMM in DMF, after precipitation from methylene chloride: DIPE and lyophilization from dioxane (2 diastereomers can be recognized by HPLC).

FAB-MS (M+H)<+> - 725; tRet(I) - 17.2 and 17.6 min.;

Rf(D) - 0.56.

a) Z - ( L) - Val - [ Phe^ N 1 e] - H • 2HC1:

Analogous to example 2a) is obtained after lyophilization

the title compound starting from 310 mg (0.53 mmol) Z-( L )-Val- [Phe^-Nle]-Boe.

<t>Ret^1) *" 16»4 min.; Rf(U) - 0.25.

b) Z-tD-Val-CPhe^Nlel-Boc:

Analogous to example 37, the title compound is obtained from 250

mg (0.71 mmol) H-CPhe^Nle]-Boe, 268 mg (1.07 mmol) Z-(L)-valln, 472 mg (1.07 mmol) BOP, 144 mg (1.07 mmol) HOBt and 7.1 ml of 0.3 M NMM 1 DMF, after chromatographic purification on silica gel with methylene chloride:methanol (40:1) and precipitation of the product-containing fractions from methylene chloride:DIPE.

tRet^i " 25.6 min.; Rf(X) - 0.17.

c) H- CPhe^ Nlel- Boc:

Analogous to example 17a), the title compound is obtained by

start from 830 mg (1.85 mmol) of N-trifluoroacetyl-[Phe^Nle]-Boc, after precipitation from methylene chloride: DIPE.

<t>Retf1) - 15'4 min.; Rf(K) - 0.54.

d) N-trlfluoroacetyl-CPhe^NleJ-Boc:

Analogous to example 16, the title connection is obtained by walking

from 1 g (3.86 mmol) 2(R)-[1'-(S)-(trifluoroacetylamino)-2'-phenylethyl]-oxirane from example 16å) and 720 mg

(3.86 mmol) tert-butyl-3-butyl-carbazate, after chromatographic purification on silica gel with methylene chloride: ether (20:1).

tRetf1) " 25»3 min.; Rf(0) - 0.43.

e) tert-butvl-3-butvl-carbazate:

Analogous to example 4b), one obtains from 18.0 g (136.2 mmol)

tert-butylcarbazate and 12.3 ml (135.2 mmol) n-butanal the corresponding tert-butoxycarbonyl hydrazone (25 g, 99*) as crude product, which is then hydrogenated as described 1 example 4a) in the presence of 10 g 5 * -lg platinum-on-charcoal and below 4 atm. hydrogen pressure. Chromatographic purification of the crude product on silica gel with hexane:acetic acid (1:1) gives the title compound.

Rf(N) - 0.44,

<i>H-NMR (200 MHz, CD3OD): 0.92 (t, J-7Hz, 3H), 1.43 (s,

9H), 1.30 to 1.50 (m, 4H), 2.75 (t, J-7Hz, 2H).

f) 2(R.S)-(N-(2-morpholinoethyl)-carbamoyl)-3-methylbutyric acid: Analogous to example 9b) one obtains from 7 g (43.7 mmol)

racemic isopropylmalonic acid monomethyl ester ("Chem. Ber.", 119, 1196 (1986)), 6.3 ml (48.1 mmol) aminoethyl morpholine, 6.6 ml (43.7 mmol) cyanophosphonic acid diethyl ester and 12, 8 mL (91.8 mmol) of triethylamine in DME, 2(R,S)-(N-(2-morpholino-ethyl)carbamoyl)-3-methyl-butyric acid methyl ester (isopropylmalonic acid-N-morpholinoethylamide methyl ester). This is stirred for 5 hours in a mixture of 28 ml of 2N caustic soda and 28 ml

dioxane at RT, acidify with 2N hydrochloric acid and evaporate completely. The residue is digested with ethanol, filtered off and yields the title compound after evaporation of the filtrate.

<*>H-NMR (200 MHz, CD30D): 0.95 and 1.00 (2d, J-7Hz, 6H), 2.25 (m, 4H), 2.70 (m, 6H), 2, 75 (d, J-8Hz, 1H), 3.45 (m, 2E), 3.75 (m, 4H).

Example 62; Z-(Lj-Val-CPhe^NleMft-CS-Ctetrazol-l-yl)-proplonyl)-Val): Analogous to example 37, the title compound is obtained from 100 mg (0.18 mmol) Z-(L)-Val-[Phe <NN>Nle]-H'2HCl (from Example 61a), 65 mg (0.27 mmol) N-(3-(tetrazol-1-yl)-proplonyl)-(L)-valine from Example 44a), 119 mg (0.27 mmol) 80P, 36 mg (0.27 mmol) HOBt and 2.1 ml 0.3 M N-methylmorpholine 1 DMF, after precipitation from methylene chloride: DIPE and lyophilization from dioxane: tert-butanol (2 diastereomers can recognized by HPLC).

FAB-MS (M+H)<+> - 708; <t>Ret(I) - 20.3 and 20.6 min.;

Rf(D) - 0.43.

Example 63: Z-(L)-Val-[Phe^NleXN-(2(R,S)-(N-(2-pyridyl-methyl)-carbamoyl)-3-methyl)-butyryl) (dibenzene sulfonate) : Analogous to example 37, the title compound is obtained by starting from 95 mg (0.17 mmol) of Z-fD-Val-CPhe^Nle]-H*2HC1 from example 61a), 60 mg (0.26 mmol) (R, S)-isopropylmalonic acid-N-(2-picolyl)-monoamide, 113 mg (0.26 mmol) BOP, 35 mg (0.26 mmol) HOBt and 2.0 ml 0.3 M NMM 1 DMF, after chromatographic purification on silica gel with methylene chloride:methanol (15:1), as free amine. This is dissolved in methylene chloride, 2 equivalents of benzenesulfonic acid are added and the product is precipitated by the addition of DIPE. Lyophilization from tert-butanol gives the dibenzenesulfonate salt (2 diastereomers can be recognized by

HPLC).

FAB-MS (M+H)<+> - 703; "tRet^) " 17»7 °8 18»° min.;

Rf(D) - 0.54.

a) Isopropylmalonic acid- N-( 2- picol. vl ) mopn«niiri •

To a solution of 15 g (93.6 mmol) of isopropylmalonic acid monomethyl ester (preparation: "Chem. Ber.", 119, 1196

(1986)) 10.6 ml (103 mmol) of N-methylmorpholin and then 13.5 ml (103 mmol) of isobutyl chloroformate are added dropwise to 1,150 ml of THF. After 30 min. 15.3 ml (150 mmol) of 2-picolylamine is added and the whole is stirred for 2 hours. The reaction mixture is diluted with methylene chloride, washed with IN sodium hydroxide solution and water, the organic phase is filtered through water and evaporated. Crystallization from the residue gives isopropylmalonic acid N-(2-picolylamide) methyl ester which is hydrolysed as described in example 61f) 1 2N caustic soda and dioxane to the title compound.

tRet(II) - 16.0 min.

Example 64; Z-(L)-Val-[Phe<NN>(p-F)Phe]*-(H-(3-(tetrazol-1-yl)-proplonyl)-(L)-Val) (benzenesulfonate): Analogous to Example 37 the title compound is obtained from 100 mg (0.16 mmol) Z-(L)-Val-[Phe<NN>(p-F)Phe]-H from example 22a), 59 mg (0.25 mmol) N-(3- (tetrazol-1-yl)-propionyl)-(L)-valine from Example 44a), 109 mg (0.25 mmol) BOP, 33 mg (0.25 mmol) HOBt and 1.19 ml 0.3 M N- methylmorpholine in DMF, after precipitation from methylene chloride: DIPE, as free amine. This is dissolved in methylene chloride:methanol, 1 equivalent of benzenesulfonic acid is added and the whole is precipitated by adding hexane. Lyophilization from tert-butanol gives the title compound as the benzenesulfonate salt.

FAB-MS (M+H)<+> - 760; tRet(I) - 21.6 min.;

Rf(B) - 0.49.

Example 65: Methyl sulfonyl-tPhe^Phe]«-( N-phenylacetyl-(L )-Val): 132 mg (0.28 mmol) Methyl sulfonyl - [Phe^Phe]-H* 2HC1 is reacted analogously to the example 7 with 197 mg (0.84 mmol) N-phenylacetyl-(L)-valine (Preparation: "Mem. Tokyo Univ. Agric.", 20, 51

(1978)), 317 mg (0.84 mmol) HBTU and 0.23 ml (1.67 mmol) triethylamine in DMF and gives the title compound after precipitation from methanol by addition of ether.

FAB-MS (M+H)<+> - 581; tRet(I) - 20.2 min.;

Rf(B) - 0.64.

a) Methyl sulfonyl - [ Phe^ Phe] - H • 2HC1:

Analogous to example 2a), the title compound is obtained as follows

lyophilization starting from 130 mg (0.28 mmol) of methyl-sulfonyl-[Phe<NNp>he]-Boe.

FAB-MS (M+H)<+> - 364; tRet(<I>I) - 28.5 min.;

Rf(K) - 0.56.

b) Methyl sulfonyl - [PheMPhe] - Boe:

Analogously to example 16a), the title compound is obtained by

start from 1.1 g (4.56 mmol) of 2(R)-[1'(S)-(methylsulfonyl-amino)-2'-phenylethyl]oxirane and 1.11 g (5.02 mmol) of tert- butyl 3-benzyl carbazate (preparation: "J. Chem. Soc. Perkin I", 1712 (1975)), as diastereomer mixture in the ratio 4:1. On crystallization from methylene chloride:hexane, the ratio is improved to 10:1 in favor of the 2S-dlaster isomer.

FAB-MS (M+H)<+> - 464; tRet(I) - 21.3 min.;

Rf (N) - 0.26.

c) 2 ( R )- Tl'( S )-(methylsulfonylamino)-2•- phenylmethylcyclohexane:

A solution of 1 g (6.8 mmol) of 1-phenyl-3-buten-2(S)-amine from example 16b) in 10 ml of methylene chloride is placed at 0°C with 2.36 g (13.6 mmol) of methanesulfonic anhydride and 1.888 ml (13.6 mmol) of triethylamine and the whole is stirred for 11 hours. The reaction mixture is washed with water and saturated sodium bicarbonate solution, the organic phase is filtered through water and evaporated and 2(S)-methylsulfonylamino-1-phenyl-3-butene is obtained. 1 g (4.4 mmol) of this crude product is dissolved in 1 30 ml of methylene chloride, 3.05 g (17.7 mmol) of 4-chloroperbenzoic acid is added at RT and the whole is stirred for 18 hours. The reaction solution is washed five times with 10 µl aqueous sodium sulfate solution, filtered through water and evaporated completely. The crude product gives 1 according to ^H-NMR the two (2R)- and (2S)-epimers in the ratio 4:1. i-H-NMR (200 MHz, CD3OD): 2.30 and 2.52 (2s, total 3E),

2.6 to 3.2 (m, 5H), 3.55 (m, 1H), 7.32 (m, 5H).

Example 66: Methoxycarbonyl - (L )-Val-[ PheIiNLeu]«-(N-methoxy-carbonyl-(L)-Val): Analogously to Example 37, the title compound is obtained from 200 mg (0.55 mmol) H-[Phe ^Leu]-H*3HC1 (from Example 13a), 291 mg (1.66 mmol) N-methoxycarbonyl-(L)-vallin (Preparation: "Chem. Lett.", 705 (1980)), 735 mg (1 .66 mmol) BOP, 225 mg (1.66 mmol) HOBt and 11 ml of 0.3 M NMM in DMF, after precipitation from methylene chloride: DIPE and lyophilization from dioxane.

FAB-MS (M+H)<+> - 566; tRet(<I>) " 18»6 min.;

Rf(U) - 0.33.

Example 67: Methoxycarbonyl -(L )-Val- [Phe^p-F )Phe]«-(N-methoxycarbonyl-(L)-Val): Analogous to example 37, the title compound is obtained from 200 mg (0.48 mmol) H-[ Phe^(p—F)Phe]-H* 3HCl (from Example 42b), 255 mg (1.45 mmol) N-methoxycarbonyl-(L)-vallin (Preparation: "Chem. Lett.", 705 (1980) ), 643 mg (1.45 mmol) BOP, 196 mg (1.45 mmol) HOBt and 9.7 ml 0.3 M NMM 1 DMF, after precipitation from methylene chloride: DIPE and lyophilization from dioxane.

FAB-MS (M+H)<+> - 618; tRet(<I>) - 19•5 min.;

Rf(U) - 0.22.

Example 68: Methoxycarbonyl - (L) - Val [ Phefflf( p-CN )Phe] «—

(N-Methoxycarbonyl)-(L)-Val):

Analogous to example 37, the title compound is obtained from 200 mg (0.48 mmol) H-CPhe^p-CNjPheil-H-SHCl (from example 47a), 250 mg (1.43 mmol) N-methoxycarbonyl-(L)-valine ( preparation: "Chem. Lett.", 705 (1980)), 631 mg (1.43 mg (1.43 mmol) BOP, 193 mg (1.43 mmol) HOBt and 9.5 ml 0.3M NMM in DMF , after chromatographic purification on silica gel with methylene chloride:methanol (15:1) and lyophilization of the product-containing fractions from dioxane.

FAB-MS (M+H)<+> - 625; tRet(I) " 18 min.;

Rf(U) 0.31.

Example 69: Z-(L)-Val-[(p-F)Phe<NH>(p-F)Phe]«-(N-(2(B,S)-(N-(2-morpholinoethyl)-carbamoyl)- 3-methyl)-butyryl): Analogous to example 18, 23.0 mg (0.089 mmol) of 2(R,S)-(N-(2-morpholinoethyl)-carbamoyl)-3-methyl-butyric acid (Example 61f) and 45 mg (0.081 mmol) Z-(L)-Val-[(p-F)Phe<NN>(p-F)Phe]-H (example

32) converted to the title compound with 33.8 mg (0.089 mmol)

HBTU in 0.76 ml NMM/CH3CN 0.25M, after which the title compound is redissolved with DMF/DIPE.

DC Rf(P) - 0.42; FAB-MS (M+H)<+> - 795.

Example 70: Z-(L)-Val-[(p-F)PheliN(p-F)Phe]«-(N-(2(R,S)-(N-(2-pyr yl)-carbamoyl)- 3-methyl)-butyryl): Analogous to example 18, 21.0 mg (0.089 mmol) of racemic isopropylmalonic acid-N-(2-picolyl)amide (Example 63a) and 45 mg (0.081 mmol) of Z-(L)-Val- [(p—F)Phe^(p—F)Phe]-H (Example 32) reacted with 33.8 mg (0.089 mmol HBTU 1 0.76 mL NMM/CH 3 CN 0.25 M) to the title compound which was then re-dissolved with DMF /DIPE.

DC Rf(P) - 0.52; FAB-MS (M+H)<+> - 773.

TTk<g>f>mp«»1 71 «

Analogous to one of the methods stated above, the following compounds can be prepared: a) Z-(L)-Val-[(p-F)Phe<NN>(p-F)Phe]<-((L)-Val)*-(N-morpholino carbonyl-Gly); b ) N-morpho inocarbonyl - (L)-Val - [ (p-F )PheNN( p-F )Phe]«-( (L) - ValK(N-morpholinocarbonyl-Gly); c) N-(quinoline-2- carbonyl)-(L)-Asn-[PheNN(p-F)Phe]<-( (L)-Val)-d) N- (mor f ol inosul f onyl )-(L) -Val - [PheNNLeu]*- ( N - (morphol ino-sulfonyl)-(L)-Val.

Example 72: Gelatin solution:

A sterile filtered aqueous solution with 2096 cyclodextrins as solution formulas, of one of the above-mentioned examples mentioned compounds with formula I as active ingredient are mixed under heating with a sterile gelatln solution which as a preservative contains phenol and under aseptic conditions, in such a way that 1.0 ml of the solution has the following composition: Active ingredient 3 mg Gelatin 150, 0 mg Phenol 4.7 mg Distilled water with 20* cyclodextrins as solvent formulas 1.0 ml Example 73; Sterile terrigen for injection: Dissolve 5 mg of one of the compounds of formula I mentioned in the above examples as active ingredient in 1 ml of an aqueous solution with 20 ml of mannitol and 20% cyclodextrin as solvent. The solution is sterile filtered and filled into 2 ml ampoules under aseptic conditions, deep-frozen and lyophilized. Before use, the lyophilisate is dissolved in 1 ml of distilled water and 1 ml of physiological saline solution. The solution is used intramuscularly or intravenously. This formulation can also be filled in 1 double-chamber syringe ampoule.

Example_74: Nasal spray:

To a mixture of 3.5 ml of Myglyol® and 0.08 g of benzyl alcohol, 500 mg of finely ground (< 5.0 µm) powder of one of the compounds with formula I as active ingredient mentioned in the above examples is suspended. This suspension is filled in a container with a dosing valve. The container is also filled with 50 g of Freon 12® under pressure through the valve. By shaking, "Freon" dissolves in the Myglyol-benzyl alcohol mixture. This spray container contains approx. 1.00 single doses that can be applied individually.

Tirkaftmpftl 7K: Varnish tablets:

For the production of 10,000 varnish tablets, each containing 100 mg of active ingredient, the following ingredients are processed:

A mixture of the compounds mentioned in the examples given above with formula I as active ingredient, 50 g of corn starch and the colloidal silicic acid is processed with starch paste from 250 g of corn starch and 2.2 kg of demineralized water into a moist mass. This is run through a sieve with a mesh size of 3 mm and dried at 45<*>C for 30 minutes in a fluid bed dryer. The dried granules are pressed through a 1 mm mesh sieve, mixed with a previously sieved mixture (1 mm sieve) of 330 g of corn starch, the magnesum stearate, stearic acid and the sodium carboxymethyl starch and pressed into slightly domed tablets.

Claims (8)

1. Compound, characterized by the general formula (I), there Ri and Rq independently of each other mean hydrogen, loweralkanoyl, phenyl-loweralkanoyl, phenyl-loweralkanoyl where the loweralkanoyl residue is substituted with carbamoyl, morpholino-loweralkanoyl, thio-morpholino-loweralkanoyl, pyridyl-loweralkanoyl, quinolyl-loweralkanoyl, tetrazolyl-loweralkanoyl, amlno-loweralkanoyl which is substituted on the amine nitrogen with N-morpholino- or N-tlomorpholinocarbonyl, halogen-lower alkanoyl containing up to 3 halogen atoms, 2-(N-morpholnolower alkyl-carbamoyl)-lower alkyl, 2-(N-pyridyl lower alkyl-carbamoyl)-lower alkanoyl . asparagine in (D)-, (L)- or (D.L)-form, where the α-amino group is unsubstituted or is acylated with one of the other up to now-mentioned Rj or Rq, provided that at most one of the residues Ri and Rq means hydrogen, <R>2, R4, Rg and Rg are hydrogen, R2, R4, Rg and Rg are hydrogen, R3 means lower alkyl, cyclohexyl-lower alkyl or optionally with halogen, lower alkoxy or cyano substituted phenyl lower alkyl, R5 means hydroxy and R7 means lower alkyl, cyclohexyl lower alkyl or optionally with halogen, lower alkoxy or cyano substituted phenyl lower alkyl, whereby lower in the definitions above means that the residues contain up to and including 7 carbon atoms, or possibly a salt thereof. 2. Compound with formula (I) According to claim 1, characterized in that Ri and R9 mean a monovalent residue of the amino acid (L)-valine bonded above the carboxy group and acylated on the amine nitrogen with benzyloxycarbonyl, R2, R4, R6 and R8 mean hydrogen, R3 means benzyl, R5 means hydroxy, R7 means isobutyl, and the carbon atoms carrying the residues R3 and R5 exist in S configuration, as well as a pharmacologically acceptable salt of one of these compounds. 3. Compound with formula (I) according to claim 1, characterized in that Ri and Rg mean a monovalent residue of the amino acid (L)-valine bonded above the carboxy group and acylated on the amine nitrogen with benzyloxycarbonyl, R2, R4, Rb and R8 mean hydrogen, R3 means benzyl, R5 means hydroxy, R7 means benzyl, and the asymmetric carbon atoms carrying the residues R3 and R5 exist in S-configuration, as well as pharmacologically acceptable salts of this compound. 4. Compound with formula (I) according to claim 1, characterized in that Ri and Rg mean the monovalent residue of the amino acid (L)-valine bonded above the carboxy group, on the amino nitrogen atom with 4-thiomorpholinocarbonyl acylated, R2, R4. R 6 and R 8 mean hydrogen, R3 means benzyl, R5 means hydroxy, R7 means isobutyl, and the asymmetric carbon atoms carrying the residues R3 and R5 exist in S configuration, as well as pharmacologically acceptable salts of this compound. 5. Compound with formula (I) according to claim 1, characterized in that Ri and Rg mean a monovalent residue of the amino acid (L)-valine bonded above the carboxy group and acylated on the amine nitrogen with benzyloxycarbonyl, R2, R4, R6 and Rg means hydrogen, R3 means benzyl, R5 means hydroxy, R7 means p-cyanobenzyl, and the asymmetric carbon atoms carrying the residues R3 and R5 exist in S configuration, as well as pharmacologically acceptable salts of this compound. 6. Compound with formula (I) according to claim 1, characterized in that Ri and Rg mean the amino acid (L)-isoleucine bonded above the carboxy group, on the amino nitrogen atom with 4-thiomorpholinocarbonyl acylated, monovalent residue of, <R>2, R4, Rg and Rg are hydrogen, R3 means benzyl, R5 means hydroxy, R7 means isobutyl, and the asymmetric carbon atoms carrying the residues R3 and R5 exist in S configuration, as well as pharmacologically acceptable salts of this compound. 7. Pharmaceutical preparation, characterized in that it contains a compound of formula (I) according to one of claims 1 to 6 or a pharmaceutically acceptable salt of such a compound with at least one salt-forming group together with a pharmaceutically acceptable carrier material. 8. Use of one of the 1 claims 1 to 6 mentioned compounds of formula (I) or a pharmaceutically acceptable salt of such a compound with at least one salt-forming group for the production of pharmaceutical preparations for inhibiting the gag protease action of HIV-1 and/ or HIV-2.